KR20240019089A - Treatment methods for patients with hepatorenal syndrome type 1 - Google Patents

Abstract

The principles and embodiments of the present disclosure relate to methods of using terlipressin to treat patients with impaired renal function associated with liver disease. Treatment of adult patients with hepatorenal syndrome type 1 (HRS-1) requires that the patient have a baseline model end-stage liver disease (MELD) score <35 or the patient have a serum creatinine (SCr) <5 mg/dl. or, if the patient has an ACLF grade <3, or a combination thereof, administering a terlipressin dose to the patient and/or determining the patient's oxygenation level before and during treatment with terlipressin ( It may include the step of monitoring SpO ₂ ).

Description

Treatment methods for patients with hepatorenal syndrome type 1

Cross-reference to related applications

This application claims the benefit of U.S. Patent Application No. 17/340,765, filed June 7, 2021, the entire contents of which are incorporated herein by reference.

Integration of sequence lists

A computer-readable text file (approximately 1 kilobyte in file size) named “105870_726724_SequenceListing_ST25.txt” created on or about June 6, 2022 contains the Sequence Listing for this application and is hereby incorporated by reference in its entirety.

technology field

The principles and embodiments of the present disclosure relate generally to methods of treating patients with type 1 hepatorenal syndrome.

Hepatorenal syndrome type 1 (HRS type 1 or HRS-1) is when acute renal failure occurs in patients with end-stage cirrhosis without any other cause. It is characterized by rapid onset of renal failure and has a high mortality rate of over 80% within 3 months. Renal failure is a confirmed complication of cirrhosis; Acute renal failure is known to have a poor prognosis in patients with cirrhosis. In various cases, renal failure may be due to hypovolemia, hepatorenal syndrome without progressive infection, or hepatorenal syndrome with progressive infection. Unfortunately, patients with HRS type 1 may die from kidney failure while waiting for a liver transplant. There is currently no way to determine which patients would benefit most from terlipressin treatment to reverse HRS type 1.

Hepatorenal syndrome (HRS) manifests as low glomerular filtration rate due to renal vasoconstriction, decreased vascular resistance due to splanchnic and peripheral arterial vasodilation, and portal hypertension. HRS is defined as cirrhosis with ascites, serum creatinine level > 133 μmol/l (1.5 mg/dL), diuretic withdrawal and no improvement in serum creatinine level after at least 2 days of volume expansion with albumin (level of ≤ 133 μmol/l). decreased to), and in the absence of shock and parenchymal renal disease. HRS type 1 is manifested by a doubling of the initial serum creatinine level to > 226 μmol/l (2.56 mg/dL) within 2 weeks.

Normal creatinine levels are 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women. Creatinine 1 mg/dl is equal to 88.4 μmol/l.

However, the specific mechanisms that maintain effective arterial blood volume and relatively normal arterial pressure in patients with cirrhosis affect renal function, such as retention of sodium and insoluble water, which can lead to ascites and edema and cause intrarenal vasoconstriction and hypoperfusion. This can cause kidney failure. Ascites may result from a combination of splanchnic artery vasodilation and portal hypertension that alter intestinal capillary pressure and permeability, facilitating the accumulation of stagnant fluid in the abdominal cavity.

A contributing factor to ascites formation is visceral vasodilation, which reduces effective arterial blood volume. Portal hypertension also occurs in cirrhotic livers due to increased hepatic resistance to portal blood flow and may cause splanchnic vasodilatation. There may be significant impairment of insoluble renal water excretion and renal vasoconstriction, leading to HRS.

In various cases, there may be signs of hepatic decompensation, including INR > 1.5, ascites, and encephalopathy. Hyponatremia is also a frequent complication in patients with cirrhosis and ascites that is associated with increased morbidity.

Systemic inflammatory response syndrome (SIRS) is an inflammatory response that is not necessarily related to infection but may initially result from non-specific damage that produces local cytokines. SIRS is typically characterized by four criteria, including: (1) core body temperature below 36°C (96.8°F) or above 38°C (100.4°F), (2) heart rate above 90 beats per minute, (3) ) tachypnea (high respiratory rate) with >20 breaths per minute; or an arterial partial pressure of carbon dioxide (CO ₂ ) less than 4.3 kPa (32 mmHg), and (4) less than 4000 cells/mm ³ (4Х10 ⁹ cells/L) or less than 12,000 cells/mm ³ (12Х10 ⁹ cells/L). L) excess white blood cell count; or the presence of more than 10% of immature neutrophils (bands), with more than 3% of bands being called bandemia or “left-shift.” SIRS can be diagnosed when two or more of these criteria are present.

Sepsis has been defined as a systemic inflammatory response to infection, and septic shock is sepsis complicated by hypotension or hyperlactatemia that is unresponsive to fluid resuscitation.

The mortality rate for patients suffering from HRS and SIRS can be quite high, approaching 70%.

Many studies have been performed on patients with end-stage liver disease and systemic inflammatory responses. HEPATOLOGY, Vol. 46, no. One study described by Thabut et al., published in 2007, concluded that the presence of SIRS criteria, with or without infection, was a major independent prognostic factor in patients with cirrhosis and acute functional renal failure.

The presence of HRS and SIRS typically indicates a short lifespan if not effectively treated with appropriate medications within a short period of time. Therefore, it is most important to identify the most effective treatment for patients presenting with specific symptoms and for patients to start an appropriate regimen as soon as possible.

Terlipressin is a synthetic analog of vasopressin with long-term effects that acts as a peptide vasopressin VIa receptor agonist. Terlipressin is a derivative of vasotocin prepared by extending the N-terminus by three amino acid residues and is used as a vasoactive drug in the management of low blood pressure. Terlipressin can be synthesized by stepwise coupling amino acids to each other in liquid or solid phase using a peptide synthesizer. Terlipressin is a prodrug that is slowly metabolized to lysine-vasopressin and in this way provides long-term biological effects. While the half-life of vasopressin is only 6 minutes (duration of action is 30 to 60 minutes), the half-life of terlipressin is 6 hours (duration of action is 2 to 10 hours).

The chemical structure of terlipressin (Gly-Lys-Pro-Cys-Asn-Gln-Phe-Tyr-Cys-Gly-Gly-Gly; SEQ ID NO: 1) in the injectable formulation is shown below.

Molecular formula: C ₅₂ H ₇₄ N ₁₆ O ₁₅ S ₂

Molecular Weight: 1227.4 daltons

Appearance: Homogeneous lyophilized white to off-white solid.

Solubility: Clear colorless solution in saline solution

Vial: Colorless glass vial containing 11 mg of white to off-white solid, 1 mg of active ingredient and 10 mg of mannitol.

The active ingredient, N—[N—(N-glycylglycyl)glycyl]-8-L-lysine vasopressin, is a cyclic nonapeptide composed of 12 amino acids and having a disulfide bridge between the 4th and 9th amino acids. It is a hormone produced by the synthesis of 8-lysine vasopressin, which has a typical ring structure. Three glycyl-amino acids are substituted at position 1 (cysteine) of 8-lysine-vasopressin. This N-terminal extension of 8-lysine-vasopressin greatly reduces the rate of metabolic degradation of the active ingredient, since the glycyl molecule inhibits rapid N-terminal enzymatic degradation. Terlipressin may be present in pharmaceutical compositions as a salt, diacetate salt, hydrate, and/or free base, such as terlipressin acetate or terlipressin diacetate pentahydrate.

The principles and embodiments of the present disclosure relate generally to methods of treating a patient with HRS-1 by administering terlipressin to the patient to achieve reversal of HRS-1. In one or more embodiments, response criteria provide a new and useful function that indicates a patient's likelihood of improved response to terlipressin administration.

Some aspects of the disclosure relate to methods of treating a patient having hepatorenal syndrome type 1 (HRS-1), wherein the patient is enumerated for transplant at baseline and has a baseline model end-stage liver disease (MELD) of less than 35. ) administering a dose of terlipressin to the patient by intravenous (IV) injection when having a score; and discontinuing or reducing the dose of terlipressin in patients with serum creatinine (SCr) ≥ 5 mg/dl and/or acute-on-chronic liver failure (ACLF) grade ≥ 3. do. Terlipressin may be administered as an IV bolus injection over 2 minutes every 6 hours.

In some aspects, the method may further include obtaining the patient's baseline MELD score. In a further aspect, the method further comprises obtaining a SCr level in the patient prior to administering the terlipressin dose to determine a baseline SCr level. In some instances, terlipressin may not be administered if baseline SCr ≥ 5 mg/dl and/or baseline ACLF grade ≥ 3. In another aspect, the patient's risk of death is reduced. A patient's position on the transplant list may or may not be impaired by terlipressin administration. In some embodiments, a patient may be at increased risk of having his or her place on the transplant list impaired or affected by administration of terlipressin. Additionally, the patient's total length of ICU stay, non-ICU stay, and/or hospital stay may be shortened. In some embodiments, terlipressin administration is continued until there is a complete or partial response. In another embodiment, discontinuing or reducing the dose of terlipressin occurs in patients with respiratory failure. Patients may also have severe kidney disease, pulmonary edema, dyspnea, or a combination of these. In various aspects, the method may further include monitoring oxygen saturation of the patient during treatment with terlipressin. Monitoring oxygen saturation reduces the occurrence of adverse events.

A further aspect of the present disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), wherein when the patient has a baseline Model End Stage Liver Disease (MELD) score of less than 35, intravenous administering a dose of terlipressin to the patient by intravenous (IV) injection, the embodiment being enumerated for transplantation. The method may further include obtaining the patient's baseline MELD score. In some embodiments, the method includes not administering, not discontinuing, or reducing the dose of terlipressin in patients with serum creatinine (SCr) ≥ 5 mg/dl and/or chronic acute liver failure (ACLF) grade ≥ 3. Additional steps that are not performed may be included.

A further aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), the method comprising obtaining a baseline Model End Stage Liver Disease (MELD) score of the patient; Obtaining an SCr level in the patient prior to administering a terlipressin dose to determine a baseline SCr level; and administering a terlipressin dose to the patient if the baseline MELD score is <35, the baseline SCr level is <5 mg/dl, and the patient's ACLF grade is <3, or a combination thereof. In some embodiments, a patient may be listed for transplant. In a further aspect, if the patient is not listed for transplant at baseline, the patient may have a MELD score > 35. Terlipressin may be administered to patients by intravenous (IV) injection.

Another aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering a dose of terlipressin to the patient by intravenous (IV) injection. Stages include, the patient is listed for transplant at baseline and the patient has a baseline model end-stage liver disease (MELD) score <35, the patient has a serum creatinine (SCr) <5 mg/dl, or the patient has ACLF Dosing only occurs if you have a grade <3, or a combination of these. In some embodiments, the method includes monitoring fluid overload in a patient during treatment with terlipressin; and reducing or discontinuing the terlipressin dose if fluid overload occurs. Additionally, the method may further include administering a diuretic to the patient and/or measuring the SCr level of the patient. It can be included.

Another aspect of the disclosure relates to a method of increasing overall survival of a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining a baseline Model End Stage Liver Disease (MELD) score of the patient; Obtaining the patient's SCr level to determine a baseline SCr level; and if the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg/dl, administering a terlipressin dose to the patient. In some embodiments, patients may be listed for transplant at baseline. In a further aspect, if the patient is not listed for transplant at baseline, the patient may have a MELD score > 35.

A further aspect of the present disclosure relates to a method of reducing overall ICU or hospital admissions in patients with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining the patient's baseline Model End Stage Liver Disease (MELD) score; steps; Obtaining the patient's SCr level to determine a baseline SCr level; and if the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg/dl, administering a terlipressin dose to the patient. In some embodiments, patients may be listed for transplant at baseline. In a further aspect, if the patient is not listed for transplant at baseline, the patient may have a MELD score > 35.

1.5 mg/dl일 때까지 테를리프레신 계속 투여하는 단계를 포함한다. 일부 양태에서, 환자는 기준선에서 이식에 대해 열거될 수 있다. 추가 양태에서, 환자가 기준선에서 이식에 대해 열거되지 않는 경우, 환자는 MELD 점수 ≥ 35를 가질 수 있다.A further aspect of the disclosure relates to a method of increasing complete response in a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining a baseline Model End Stage Liver Disease (MELD) score for the patient; Obtaining the patient's SCr level to determine a baseline SCr level; administering a terlipressin dose to the patient by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg/dl; measuring the patient's SCr level during administration of terlipressin; and the patient's SCr level.

Continuing to administer terlipressin until the level is 1.5 mg/dl. In some embodiments, patients may be listed for transplant at baseline. In a further aspect, if the patient is not listed for transplant at baseline, the patient may have a MELD score > 35.

A further aspect of the disclosure relates to a method of increasing partial response in a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining a baseline Model End-Stage Liver Disease (MELD) score for the patient; Obtaining the patient's SCr level to determine a baseline SCr level; administering a terlipressin dose to the patient by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg/dl; measuring the patient's SCr level during administration of terlipressin; and continuing to administer terlipressin until the patient experiences a greater than 20% improvement in serum creatinine. Dosing may be continued until the patient experiences a greater than 30% improvement in serum creatinine. In some embodiments, patients may be listed for transplant at baseline. In a further aspect, if the patient is not listed for transplant at baseline, the patient may have a MELD score > 35.

Another aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terripressin by intravenous (IV) injection. If a patient is listed for liver transplantation with a MELD score ≥35, the patient may be excluded from treatment.

A further aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terripressin by intravenous (IV) injection. , where patients are treated only if they belong to a patient population with a median waiting time from listing to transplant of 5.6 months or more.

Another aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection. , where the patient is excluded from treatment if he or she belongs to the patient population with a median waiting time from listing to transplant of 0.23 months or less.

Some aspects of the disclosure relate to methods of treating patients with hepatorenal syndrome type 1 (HRS-1), the methods comprising reducing a risk selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof. Reducing the population of patients eligible for treatment to a palliative population to reduce the population; and administering a dose of terripressin to the patient in the palliative population by intravenous (IV) injection.

A further aspect of the disclosure relates to a method of administering terlipressin to treat a patient having hepatorenal syndrome type 1 (HRS-1), wherein the patient has a baseline model end-stage liver disease (MELD) of less than 35. Listed for transplantation in the score, the method includes administering a dose of terlipressin to the patient by intravenous (IV) injection; and discontinuing or reducing the dose of terlipressin in patients with a serum creatinine (SCr) level > 5 mg/dl and/or chronic acute liver failure (ACLF) grade > 3. In some embodiments, the method further comprises obtaining a SCr level in the patient prior to administering the terlipressin dose to determine a baseline SCr level. The patient's risk of death may be reduced. The patient's position on the transplant list may or may not be affected. The patient's total length of ICU stay, non-ICU stay, and/or hospital stay may be shortened. In some embodiments, terlipressin administration is continued until there is a complete or partial response. In another embodiment, discontinuing or reducing the dose of terlipressin occurs in patients with respiratory failure. Patients may also have severe kidney disease, pulmonary edema, dyspnea, or a combination of these. Terlipressin may be administered as an IV bolus injection over 2 minutes every 6 hours. In some embodiments, the method may further include monitoring the patient's oxygenation level via pulse oximetry during treatment with terlipressin. Monitoring oxygenation levels reduces the occurrence of adverse events.

Some aspects of the disclosure relate to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising: obtaining a baseline oxygenation level (SpO ₂ ) via pulse oximetry; Administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient is not suffering from hypoxia; and monitoring the patient's SpO ₂ during treatment with terlipressin. Monitoring oxygenation levels can reduce the occurrence of adverse events. In some embodiments, the patient's oxygen saturation is monitored for hypoxia. The method may further include discontinuing or reducing the dose of terlipressin if hypoxia is detected. For example, terlipressin may not be administered or may be discontinued if the patient's SpO ₂ is less than 90% or the patient's FiO ₂ is greater than 0.36 at baseline or during treatment. The patient's SpO ₂ may be monitored at least three times per day during administration of terlipressin.

A further aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection. ; and discontinuing or reducing the dose of terlipressin in patients with serum creatinine (SCr) > 5 mg/dl. A further aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), the method comprising measuring serum creatinine (SCr) levels in the patient; and administering a terlipressin dose to the patient if the patient has a serum creatinine (SCr) <5 mg/dl, and the patient has an ACLF grade <3, or a combination thereof. Terlipressin may be administered to patients by intravenous (IV) injection. A further aspect of the disclosure relates to a method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection. and dosing does not occur if the patient has a serum creatinine (SCr) ≧5 mg/dl, the patient has an ACLF grade ≧3, or a combination thereof. In another aspect, the invention relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient a dose of terlipressin by intravenous (IV) injection. and administration occurs only if the patient has a serum creatinine (SCr) <5 mg/dl, the patient has an ACLF grade <3, or a combination thereof. The method includes monitoring the patient for fluid overload during treatment with terlipressin; and reducing terlipressin treatment if fluid overload occurs. As used herein, the terms “terlipressin treatment reduction” and “terlipressin dose reduction” refer to lowering the terlipressin dose, blocking the terlipressin dose, and/or reducing the terlipressin dose when the patient has previously increased the dose. This may include not increasing the dose when prescribed or scheduled at the prescribed dose. Interrupting the terlipressin dose may include temporarily blocking the dose until adverse events subside, until further notice, or until the patient's serum creatinine (SCr) is ≥ 5 mg/dl. . In a further aspect, the method may further include measuring the patient's SCr level. In some embodiments, the total length of a patient's ICU stay, non-ICU stay, and/or hospital stay can be shortened. Terlipressin administration may be continued until a complete or partial response is achieved.

In a further aspect, a method of treating a patient having hepatorenal syndrome type 1 (HRS-1) comprises administering to the patient a dose of terlipressin by intravenous (IV) injection; and managing fluid overload by reducing or discontinuing albumin, other fluid administration, and/or cautious use of diuretics. As used herein, prudent use of a diuretic means use of an effective amount of the diuretic. For clarity, reducing albumin administration may include lowering the dose or blocking administration of albumin. If fluid overload persists, treatment methods may further include reducing or discontinuing terlipressin treatment. In a further aspect, managing fluid overload can reduce mortality or the incidence of adverse events in a patient or patient population receiving treatment according to the invention described herein. In another aspect, a method of treating a patient having hepatorenal syndrome type 1 (HRS-1) includes administering to the patient a dose of terlipressin by intravenous (IV) injection; and managing fluid overload by reducing or discontinuing albumin, other fluid administration, and/or cautious use of diuretics, wherein the patient suffers from respiratory failure, severe renal disease, pulmonary edema, dyspnea, tachypnea, ischemia, or these. It additionally has a combination of .

In a further aspect, a method of treating a patient having hepatorenal syndrome type 1 (HRS-1) comprises administering to the patient a dose of terlipressin by intravenous (IV) injection, The dose is not increased in the presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, progressive significant adverse events, pre-existing severe coronary artery disease, or any combination thereof. In a further aspect, a method of treating a patient having hepatorenal syndrome type 1 (HRS-1) comprises administering to the patient a dose of terlipressin by intravenous (IV) injection, The dose is reduced or discontinued in the presence of fluid overload, pneumonia, bronchospasm, pulmonary edema, progressive significant adverse events, pre-existing severe coronary artery disease, or a combination thereof. Another aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient every 6 hours by intravenous (IV) bolus injection over 2 minutes. administering a dose of terlipressin; Monitoring the patient for fluid overload during treatment with terlipressin; and, reducing or discontinuing terlipressin treatment if fluid overload persists.

Ischemic events (e.g., inadequate blood supply to the skin, heart, blood vessels, or gastrointestinal tissues) may occur following terlipressin administration. The most common ischemia-related adverse events may include skin discoloration, cyanosis, intestinal ischemia, and combinations thereof. Severe ischemic events in patients treated with terlipressin may include intestinal ischemia, vascular skin disorders, cyanosis, reticuloderma, myocardial infarction, poor peripheral circulation, myocardial ischemia, or a combination of these. Terlipressin should be used with caution in patients with a history of ischemic events and certain cardiac diseases. For patients who experience signs or symptoms suggestive of ischemic adverse reactions, the terlipressin dose should be reduced or permanently discontinued. A further aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient every 6 hours by intravenous (IV) bolus injection over 2 minutes. It includes administering a dose of terlipressin, and in patients with ischemia, reducing or discontinuing terlipressin treatment. In another aspect, the invention includes a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising treating the patient every 6 hours by intravenous (IV) bolus injection over 2 minutes. Administering a dose of terlipressin to the patient, wherein the treatment reduces or discontinues the terlipressin dose if the patient has skin, heart, vascular, gastrointestinal ischemia, or a combination thereof. The terms “ischemia” and “ischemic event” may be used interchangeably.

Another aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising treating the patient every 6 hours by intravenous (IV) bolus injection over 2 minutes. administering a terlipressin dose to the patient, wherein the terlipressin dose is not increased in the presence of fluid overload, pneumonia, bronchospasm, or pulmonary edema. A further aspect of the disclosure relates to a method of treating a patient with hepatorenal syndrome type 1 (HRS-1), comprising administering to the patient every 6 hours by intravenous (IV) bolus injection over 2 minutes. administering a dose of terlipressin; Monitoring the patient for fluid overload during treatment with terlipressin; and reducing or discontinuing the terlipressin dose if fluid overload occurs. In another aspect of the disclosure, a method of treating a patient with hepatorenal syndrome type 1 (HRS-1) includes administering Terlipre to the patient every 6 hours by intravenous (IV) bolus injection over 2 minutes. Terlipressin treatment should be discontinued immediately if a new dose is administered and there is post-treatment pulmonary edema, new-onset or worsening pneumonia, or unresolved hepatic encephalopathy ≥ grade 3 with risk of aspiration.

A further aspect of the disclosure relates to a method of increasing overall survival or patients having hepatorenal syndrome type 1 (HRS-1), the method comprising measuring serum creatinine (SCr) levels in the patient; and administering a terlipressin dose to the patient if the patient has a serum creatinine (SCr) <5 mg/dl. A further aspect of the present disclosure relates to a method of reducing overall ICU or hospital admissions in patients with hepatorenal syndrome type 1 (HRS-1), the method comprising measuring serum creatinine (SCr) levels in the patient; and administering a terlipressin dose to the patient if the patient has SCr <5 mg/dl.

A further aspect of the disclosure relates to a method of increasing complete response in a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising measuring serum creatinine (SCr) levels in the patient; administering a terlipressin dose to the patient by intravenous (IV) injection if the patient's SCr level is <5 mg/dl; and the patient's SCr level. Continuing to administer terlipressin until the level is 1.5 mg/dl. Another aspect of the disclosure relates to a method of increasing partial response in a patient with hepatorenal syndrome type 1 (HRS-1), the method comprising measuring serum creatinine (SCr) levels in the patient; administering a terlipressin dose to the patient by intravenous (IV) injection if the patient's SCr level is <5 mg/dl; and continuing to administer terlipressin until the patient experiences a greater than 20% improvement in serum creatinine.

Additional aspects and features are set forth in part in the following description, and will become apparent to those skilled in the art upon review of the specification, or may be learned through practice of the disclosed subject matter.

Additional features, characteristics and various advantages of embodiments of the invention, which also illustrate the best mode contemplated by the applicant, will become more apparent upon consideration of the following detailed description taken in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout; here:
1 illustrates an exemplary implementation of a terlipressin treatment protocol;
Figure 2 illustrates an exemplary implementation of a terlipressin treatment protocol;
Figure 3 illustrates a set of unexpected results from an exemplary implementation of a terlipressin treatment protocol;
Figure 4 illustrates an exemplary implementation of a terlipressin treatment protocol;
Figure 5 is a graph showing 90-day survival of patients treated and untreated with terlipressin according to ACLF grade;
Figure 6A shows the percentage of patients with renal failure at baseline and end of treatment for patients treated with terlipressin and placebo;
Figure 6B shows the percentage of patients in respiratory failure at baseline and end of treatment for patients treated with terlipressin and placebo; and
Figure 6C shows the percentage of patients with respiratory failure with ACLF grade ≤ 2 and ACLF grade ≥ 3 for patients treated with terlipressin and placebo.

The principles and embodiments of the present disclosure relate to methods of improving renal conditions in patients following a treatment protocol comprising terlipressin. Accordingly, various embodiments of the present disclosure provide methods of treating a patient with terlipressin or terlipressin and albumin.

As used herein, the use of “terlipressin” may refer to terlipressin or its salt, diacetate salt, hydrate, and/or free base. For example, uses of terlipressin may include terlipressin acetate or terlipressin diacetate pentahydrate. In a further example, terlipressin may refer to any other suitable salt or hydrate thereof or any other biologically acceptable salt or hydrate thereof.

As used herein, the terms “terlipressin treatment reduction” and “terlipressin dose reduction” refer to lowering the terlipressin dose, blocking the terlipressin dose, and/or reducing the terlipressin dose when the patient has previously increased the dose. This may include not increasing the dose when prescribed or scheduled at the prescribed dose. Interrupting the terlipressin dose may include temporarily blocking the dose until adverse events subside, until further notice, or until the patient's serum creatinine (SCr) is ≥ 5 mg/dl. .

As used herein, the “remission population” or “subset of patients” includes HRS-1 patients with baseline ACLF grade 0-2, baseline serum creatinine <5 mg/dL, and/or baseline MELD <35. For example, the remission population excludes patients with baseline ACLF grade 3, baseline serum creatinine ≥5 mg/dL, and/or patients on the transplant list at baseline with baseline MELD ≥35.

In embodiments of the present disclosure, patients are evaluated to determine the specific disease and/or syndrome suffering from and to initiate a treatment regimen for the patient that would benefit from terlipressin administration.

In various embodiments, the patient has end-stage liver disease complicated by acute renal failure, such as HRS, and is treated with terlipressin.

In various embodiments, end-stage liver disease may be cirrhosis or fulminant liver failure. In various embodiments, end-stage liver disease is complicated by impaired renal function.

HRS-1 in decompensated cirrhosis is associated with hemodynamic abnormalities. Terlipressin improves renal perfusion in HRS-1 by increasing intravascular volume through splanchnic vasoconstriction. In some embodiments, terlipressin may be more effective than placebo in albumin-treated patients with decompensated cirrhosis and HRS-1. Aspects of the present disclosure relate to methods of diagnosing patients showing improved response to terlipressin treatment as indicated by increased probability of HRS reversal.

A method of identifying patients with HRS-1 who have an increased likelihood of responding to a terlipressin treatment regimen is to determine that the patient has end-stage survival disease and impaired renal function, and that the patient also meets at least 2 of the 3 criteria for SIRS. This includes confirming that the 3 response criteria are (1) white blood cell count (WBC) less than 4,000 cells/mm ³ or greater than 12,000 cells/mm ³ and (2) beats per minute (BPM). heart rate exceeding 90 beats per minute, and/or (3) HCO ₃ <21 mmol/L, with HCO ₃ being considered a surrogate measure that approximates the response criterion of arterial partial pressure of carbon dioxide (PaCO ₂ )<32 mmHg. In various embodiments, a heart rate > 85 BPM and/or HCO ₃ < 23 mmol/L may be applied as response criteria.

Aspects of the disclosure relate to terlipressin for use in the treatment of HRS-1 in a subject who also exhibits at least two of the following three response criteria:

(a) white blood cell count (WBC) less than 4,000 cells/mm ³ or greater than 12,000 cells/mm ³ ;

(b) heart rate exceeding 90 beats per minute (BPM), and

(c) HCO ₃ < 21 mmol/L, where HCO ₃ is considered a surrogate measure that approximates the response criterion of arterial partial pressure of carbon dioxide (PaCO ₂ ) < 32 mmHg. In various embodiments, one or more single doses of terlipressin are administered to a subject to treat HRS-1.

In various embodiments, the initial terlipressin dose ranges from about 0.5 mg to about 2.0 mg and is administered to the patient in a series of single doses every 4 to 6 hours, such that the patient receives terlipressin ranging from about 0.5 mg to about 2.0 mg. After receiving a single dose of Xin, receive another single dose 4 to 6 hours later. In various embodiments, a patient may receive 4 to 6 doses over a 24-hour period, where each dose ranges from about 0.5 mg to about 2.0 mg. In various embodiments, the total dose does not exceed 4.0 mg over a 24-hour period.

As shown in Figure 1, an exemplary embodiment of a method of treating a patient via an embodiment of a terlipressin treatment protocol.

In various embodiments, patients initially identified as having end-stage liver disease for whom treatment with a vasodilator may provide improvement in renal function are tested to determine the extent of the patient's cirrhosis and renal failure.

In 110 , the patient is initially identified as having end-stage liver disease and impaired renal function. In various embodiments, the patient may be suffering from cirrhosis or fulminant liver failure, wherein the patient identified as having cirrhosis may have a Child-Pugh score of A, B, or C. In various embodiments, patients with cirrhosis with a Child-Pugh score of B or C may be considered viable candidates for terlipressin treatment. In various embodiments, patients with cirrhosis with a Child-Pugh score of C may be considered viable candidates for terlipressin treatment. Various complications of end-stage liver disease, especially cirrhosis, are recognized and the prognosis is very poor.

In one or more embodiments, a treatment protocol comprising a terlipressin dose surprisingly provides reversal of one or more complicating factors, such as vasodilation, and reduces mortality due to associated complications within a 90-day window of starting treatment.

In one or more embodiments, the terlipressin treatment protocol includes identifying a patient with end-stage liver disease and impaired renal function, wherein the identified patient comprises administering terlipressin, and wherein the patient meets one of three response criteria. Determine whether the patient presents with at least 2 uncontrolled infections, sepsis, or septic shock, and if the patient is excluded from terlipressin treatment, the amount effective in improving renal function and excluding the patient from terlipressin treatment. Patients may benefit from starting terlipressin treatment by administering a daily dose of terlipressin, with improvements in renal function including a reduction in SCr of at least 25% from baseline, reversal of HRS (when SCr levels are defined as a decrease to 1.5 mg/dl) and/or confirmed HRS reversal (at least 48 hours apart). defined as two serum creatinine values of 1.5 mg/dL).

In one or more embodiments, the patient is alive 90 days after initiation of terlipressin treatment. For example, patients who experience HRS reversal, assayed HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin have at least a 60%, 65%, or 70% chance of survival at 90 days. You can. In another embodiment, the patient is alive and has not received a transplant 90 days after initiation of terlipressin treatment. For example, patients who experience HRS reversal, assayed HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin have at least a 35%, 40%, 40% chance of being alive and transplant-free at 90 days. , or it could be 45%.

In one or more embodiments, the terlipressin dosage is from about mg to about 10 mg, or from 0.5 mg to about 5.0 mg, or from 0.5 mg to about 2.0 mg, or from 0.5 mg to about mg, or from about 1.0 mg per single dose. It may range from about 2.0 mg. In various embodiments, the injectable agent may be administered intravenously as a slow bolus injection over 2 minutes, where the dose may be repeated every 4 to 6 hours. On the fourth day of therapy (after at least 10 doses), if SCr has decreased but is less than 30% of baseline values, the dose may be increased to 2 mg every 6 hours (±30 minutes) (8 mg/day). If the subject has coronary artery disease; Alternatively, the dose cannot be increased in the clinical setting of circulatory overload, pulmonary edema, or refractory bronchospasm. The terms “circulatory overload” and “fluid overload” may be used interchangeably. In various embodiments, if dosing is interrupted due to non-ischemic adverse events, terlipressin can be resumed at the same or lower dose (i.e., 0.5 to 1 mg q6h).

180 , patients with undiagnosed end-stage liver disease and impaired renal function are excluded from terlipressin treatment.

In one or more embodiments, the patient is tested for three specific response criteria, where the criteria are (1) whether the white blood cell count (WBC) is less than 4,000 cells/mm ³ or greater than 12,000 cells/mm ³ ; (2) ) includes determining whether the patient has a heart rate exceeding 90 beats per minute (BPM), and/or (3) whether the patient has tachypnea exceeding 20 breaths per minute or HCO ₃ <21 mmol/L. and HCO ₃ is considered a surrogate measure that approximates the response criterion of arterial partial pressure of carbon dioxide (PaCO ₂ )<32 mmHg. In various embodiments, the response criterion of a patient's core temperature of less than 36°C (96.8°F) or greater than 38°C (100.4°F) is not measured or considered in determining whether the patient has two or more response criteria. In some examples, response criteria may be SIRS criteria. In various implementations, criteria may be tested in any order.

At 120 , the patient is tested to determine whether the patient's WBC is <4,000 or >12,000 cells/mm ³ . In various embodiments, the test specifically relates to determining whether the patient's white blood cells are less than 4000 cells/mm ³ (4Х10 ⁹ cells/L) or more than 12,000 cells/mm ³ (12Х10 ⁹ cells/L). will be. In various embodiments, a patient will be considered to meet response criteria if the patient's WBC is <5,000 or >12,000 cells/mm ³ . In various embodiments, patients are not tested for the presence of more than 10% immature neutrophils (banded form). In various embodiments, the testing method for determining WBC can be any method known in the art.

Even if the patient's WBC is found to be within the range of 4,000 to 12,000 cells/mm ³ , the patient may still be diagnosed with SIRS if the patient meets the other two response criteria.

In various embodiments, patients with a WBC of <4,000 or >12,000 cells/mm ³ are considered to meet the response criteria.

At 130 , a patient whose WBC is within the range of 4,000 to 12,000 cells/mm ³ is tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria. The testing method for determining a patient's heart rate may be any method known in the art.

In various embodiments, patients with a WBC outside the range of 5,000 to 12,000 cells/mm ³ are tested to determine if the patient's heart rate is >90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria.

185 , patients who do not have both a WBC <4,000 or >12,000 cells/ ^mm3 and a heart rate >90 BPM are considered ineligible for two of the three response criteria and therefore a requirement to be treated with terlipressin. does not meet Patients who do not meet at least two of the three response criteria are excluded from terlipressin treatment. Such patients may instead be treated with one or more other pharmacological agents such as norepinephrine, vasopressin, or a combination of midodrine and octreotide. Alternatively or in addition, any of the following may be used: N-acetylcysteine, misoprostol, and/or BQ123. Another option is a transjugular intrahepatic portosystemic shunt (TIPS). Renal support in the form of dialysis is commonly administered to manage acute fluid overload in patients with HRS-1, especially when pharmacological therapy fails. The only effective and permanent treatment for end-stage cirrhosis and HRS is liver transplantation.

In 140 , patients with a WBC outside the range of 4,000 to 12,000 cells/mm ³ or a heart rate >90 BPM were tested to determine whether the patient had a respiratory rate >20 beats per minute or HCO ₃ <21 mmol/L. If the patient has a respiratory rate > 20 minutes or HCO ₃ < 21 mmol/L, the patient will be considered to meet the response criteria. In various embodiments, patients with HCO ₃ <23 mmol/L will be considered to meet the response criteria. The test method for determining a patient's respiratory rate or HCO ₃ may be any method known in the art.

In various embodiments, patients with a WBC outside the range of 5,000 to 12,000 cells/mm ³ are tested to determine whether the patient has a respiratory rate >20 breaths per minute or HCO ₃ <21 mmol/L. If the patient has a respiratory rate >20 breaths per minute or HCO ₃ <21 mmol/L, the patient will be considered to meet the response criteria. In various embodiments, patients with HCO ₃ <23 mmol/L will be considered to meet the response criteria.

In one or more embodiments, if the patient has a WBC outside the range of 4,000 to 12,000 cells/mm ³ and the patient has a respiratory rate > 20 minutes or HCO ₃ < 21 mmol/L, the patient meets 2 of 3 response criteria. It is considered suitable for branching and therefore meets the requirements for treatment with terlipressin unless otherwise excluded.

If the patient has a heart rate >90 BPM and a respiratory rate >20 breaths per minute or HCO ₃ <21 mmol/L, the patient is considered to meet 2 of the 3 response criteria and will therefore be tested unless otherwise excluded. Meets the requirements for treatment with rlipressin.

At 135 , a patient with a WBC outside the range of 4,000 to 12,000 cells/mm ³ but without a respiratory rate > 20 minutes or HCO ₃ < 21 mmol/L is tested to determine if the patient's heart rate is > 90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria.

In one or more embodiments, the patient has a WBC outside the range of 5,000 to 12,000 cells/mm ³ , but the patient does not have a respiratory rate > 20 minutes or an HCO ₃ < 21 mmol/L, wherein the patient has a heart rate > 90 BPM. If the patient's heart rate is >90 BPM, the patient will be considered to meet the response criteria. In various embodiments, patients with a heart rate >85 BPM will be considered to meet the response criteria.

If the patient has a respiratory rate >20 breaths per minute or HCO ₃ < 21 mmol/L and a heart rate > 90 BPM and the patient has a respiratory rate > 20 breaths per minute or HCO ₃ < 21 mmol/L, the patient has 3 You are considered to meet 2 of the response criteria and therefore meet the requirements for treatment with terlipressin unless otherwise excluded.

186 , patients who do not (1) have a respiratory rate > 20 breaths per minute or HCO ₃ < 21 mmol/L and (2) have a heart rate > 90 BPM are considered not meeting at least 2 of the 3 response criteria. Therefore, the requirements for treatment with terlipressin are not met. Patients who do not meet at least two of the three response criteria are excluded from terlipressin treatment. Optional alternative treatments for such patients are described above.

Although tests for response criteria are discussed in a specific order for example implementations, the tests may be performed in any specific order.

In one or more embodiments, temperature is not a response criterion because patient temperature may not provide an accurate indication of patient response to terlipressin. In various embodiments, patient temperature is excluded from the response criteria set.

In 150 , patients who have end-stage liver disease with impaired renal function and meet at least two of the three response criteria are started on terlipressin. In one or more embodiments, patients with uncontrolled infection, sepsis, or septic shock are excluded from terlipressin treatment. In various embodiments, terlipressin is administered to the patient for 1 to 4 days. In various embodiments, the patient is administered terlipressin for 4 days, unless the patient experiences an adverse event. In various embodiments, terlipressin is administered to the patient as an IV drip.

In one or more embodiments, the terlipressin treatment protocol comprises administering a terlipressin dose of about 0.1 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg by IV drip over about 4 hours to about 6 hours. to about 2.0 mg, or about 0.5 mg to about 1.0 mg, or about 1.0 mg to about 2.0 mg.

In one or more embodiments, the patient is administered terlipressin by IV about every 4 to 6 hours for 1 to 4 days. In various embodiments, terlipressin can be administered for at least 4 days.

In one or more embodiments, the patient is administered terlipressin as a slow bolus over 2 minutes approximately every 4 to 6 hours for 1 to 4 days. In various embodiments, terlipressin can be administered for at least 4 days.

At 160 , a patient receiving terlipressin is tested at least once during a 1- to 4-day dosing period to determine whether the patient responds to terlipressin. In various embodiments, the patient is administered once before starting terlipressin administration to establish a baseline and once during 1 to 4 days of terlipressin administration, or once starting terlipressin administration to establish a baseline. It can be tested once before and once in the last 4 days of terlipressin administration. In various embodiments, the patient's creatinine level determines whether the patient's serum creatinine has decreased and is greater than or equal to about 1.0 mg/dL from the patient's initial baseline value, or in the range of about 1.0 mg/dL to about 2.0 mg/dL. A decrease in level, or about 1.7 mg/dL, indicates an improvement in kidney function and is measured to determine whether the patient is responding to terlipressin.

In various embodiments, the improvement in kidney function is manifested by a decrease in serum creatinine levels of about 25% or about 30% in patients receiving terlipressin.

In one or more embodiments, the patient may have their serum creatinine level measured once daily or once every other day for each of a four-day period after starting terlipressin administration, wherein the measurement is made on the first day of terlipressin administration. can be recorded and used as the baseline creatinine level.

In various embodiments, the methods include testing the patient's SCr level during days 1 to 4 of terlipressin administration and determining whether there is a decrease in the patient's SCr level by the end of days 1 to 4 of terlipressin administration. can do.

Serum creatinine levels can be measured by any method known in the art, such as the Jaffe reaction using alkaline picrate.

GFR can be tracked by scavenging capacity studies of exogenous markers such as inulin, iohexol, iopalumate, and Cr51-EDTA, or by creatinine testing by reference methods based on isotope dilution-mass spectrometry (IDMS). It can be measured directly by estimated glomerular filtration rate (eGFR) using the method.

In 170 , a patient who tests positive for terlipressin administration, as evidenced by a decrease in the patient's serum creatinine level, receives from about 0.1 mg to about 10 mg, or from 0.5 mg to about 5.0 mg, or from 0.5 mg to about 2.0 mg, or for terlipressin in doses ranging from about 0.5 mg to about 1.0 mg, or from about 1.0 mg to about 2.0 mg. In various embodiments, the dosage administered to the patient can be adjusted based on the measured serum creatinine level(s). In various embodiments, a patient being administered terlipressin may have his or her serum creatinine levels monitored for the entire period the patient is receiving terlipressin. In one or more embodiments, the patient's serum creatinine level may be tested daily, every other day, every three days, or every four days to determine whether the patient is still responding positively to terlipressin treatment.

In various embodiments, if the SCr decreases to <1.5 mg/dL during the first 2 to 3 days of treatment, the patient's terlipressin dose increases from about 0.5 mg to about 2 to 3 days after administering terlipressin to the patient. 1.0 mg, can be increased from about 1.0 mg to about 2.0 mg.

In various embodiments, the dosage may be repeated every 4 to 6 hours for a period of 1 day or more until the patient shows recovery, or until the patient shows no further improvement. Terlipressin may be administered to the patient for a period of time ranging from about 2 days to about 16 days, or for a period of time ranging from about 4 days to about 8 days. In various embodiments, the period of time ranges from about 7 days. In various embodiments, terlipressin treatment may be continued until there is a complete response. In various embodiments, the duration of treatment of a patient with terlipressin can be from 1 to 28 days.

In 190 , patients who do not see improvement by the end of 4 days can discontinue terlipressin, in which case improvement is indicated by a decrease in eye serum creatinine levels over 1 to 4 days of terlipressin administration. . In various embodiments, patients may be tested on day 3 or 4 after starting treatment with terlipressin to determine if there is a decrease in serum creatinine levels indicative of response to treatment.

In one or more embodiments, the patient is provided with 2 days of anti-infective therapy for the documented or suspected infection prior to starting terlipressin administration if the infection is suspected. In various embodiments, a terlipressin treatment protocol may be initiated following administration of an anti-infective therapy to a patient.

Figure 2 illustrates an exemplary implementation of a terlipressin treatment protocol.

The principles and embodiments of the present disclosure also relate to providing terlipressin as an IV every 4 to 6 hours to patients identified as having HRS-1 and two or more of the three specific response criteria.

In one or more embodiments, the patient has (1) a white blood cell count (WBC) <4 or >12 cells/μL; (2) Heart rate (HR) >90 beats per minute (bpm) and (3) HCO ₃ <21 mmol/L.

Non-SIRS patients are defined as subjects with response criteria <2 as described above.

In various embodiments, temperature is not used as a response criterion.

In one or more embodiments of the disclosure, terlipressin is administered to patients exhibiting a specific set of symptoms to alleviate renal vasoconstriction and improve renal function as indicated by a decrease in serum creatinine levels of about 1.7 mg/dL from initial baseline. is administered to

At 210 , one or more patients who may exhibit end-stage liver disease are tested to determine whether they are suffering from cirrhosis with ascites and have a serum creatinine level > 133 μmol/l. Patients confirmed to have HRS undergo additional testing and/or have their medical history checked to determine whether the initial serum creatinine level has doubled to >226 μmol/l within 2 weeks, indicating type 1 HRS.

Patients with HRS-1 and at least two of the three response criteria surprisingly showed an improved response to terlipressin treatment compared to non-SIRS HRS-1 patients, as indicated by reversal of HRS signs. Additionally, patients with HRS-1, at least two of the three response criteria, and no uncontrolled infection, sepsis, or septic shock surprisingly had an improved response to terlipressin treatment compared to non-SIRS HRS-1 patients. showed it Signs of HRS may include serum creatinine levels.

Patients with HRS-1 and SIRS may experience HRS reversal, verified HRS reversal, or greater than 30% improvement in SCr after receiving terlipressin. In one or more embodiments, the patient is alive 90 days after initiation of terlipressin treatment. For example, patients who experience HRS reversal, assayed HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin have at least a 60%, 65%, or 70% chance of survival at 90 days. You can. In another embodiment, the patient is alive and has not received a transplant 90 days after initiation of terlipressin treatment. For example, patients who experience HRS reversal, assayed HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin have at least a 35%, 40%, 40% chance of being alive and transplant-free at 90 days. , or it could be 45%.

220 , once a patient is confirmed to be suffering from HRS-1, the patient is tested to determine whether the same patient exhibits at least two of the three criteria indicative of SIRS, where the three criteria are (1) WBC < 4 or >12 cells/μL; (2) HR>90 bpm, and (3) HCO ₃ <21 mmol/L.

In various embodiments, patients who are not confirmed to exhibit at least two of the three response criteria in addition to HRS-1 are excluded from the terlipressin treatment protocol. Patients with HRS-1 and demonstrating at least 2 of the 3 response criteria surprisingly improved on terlipressin treatment compared to non-SIRS HRS-1 patients, as indicated by reversal of HRS signs as shown in Figure 3 showed a positive reaction.

At 230 , patients identified as having HRS-1 and exhibiting at least two response criteria are tested to determine whether they may have uncontrolled infection, sepsis, or septic shock, where Hemorrhagic shock is excluded from the terlipressin treatment protocol.

In 240 , patients with HRS-1, at least 2 of 3 response criteria, and no uncontrolled infection, sepsis, or septic shock are initiated on terlipressin treatment. In one or more embodiments, terlipressin treatment is initiated within 48 hours of initial diagnosis that the patient has HRS-1 and at least two of the three response criteria. In various embodiments where the determination of whether the patient has uncontrolled infection, sepsis, or septic shock occurs 48 hours after initial diagnosis of both HRS-1 and response criteria, the treatment protocol is initiated within 48 hours of initial diagnosis; Treatment may be terminated if uncontrolled infection, sepsis, or septic shock appears or is determined.

In various embodiments, a baseline serum creatinine level for a patient can be determined prior to starting administration of terlipressin to the patient; Terlipressin administration was initiated within 2, 3, or 4 days of determining the baseline serum creatinine level. In various embodiments, a patient may be tested at least once daily within 4 days of starting terlipressin administration to determine whether the patient exhibits a decrease in serum creatinine level compared to a previously determined baseline serum creatinine level.

At 250 , the patient's terlipressin treatment is initiated and the patient receives a dose of terlipressin. In one or more embodiments, terlipressin may be administered to a patient as a slow infusion over a 24-hour period, where the dose over a 24-hour period may range from about 2.0 mg to about 12 mg. In various embodiments, the dosage over a 24-hour period may range from about 2.0 mg to about 4.0 mg. In various embodiments, terlipressin is administered as a continuous intravenous (IV) drip lasting from about 4 hours to about 6 hours and comprising a dose of about 0.5 mg to about 2.0 mg.

In one or more embodiments, the terlipressin dosage may be a dose of about 0.5 mg to about 2.0 mg administered intravenously every 4 to 6 hours as a slow bolus injection over 2 minutes. The dosage is given by slow IV bolus injection about every 4 hours, about every 5 hours, about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, or It may be administered approximately every 12 hours. In at least one example, doses may be administered by slow IV bolus injection approximately every 6 hours. The bolus injection may be given over about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes. In at least one example, the bolus injection may be given over about 2 minutes.

In one or more embodiments, terlipressin is used to treat patients who exhibit HRS-1 and at least two of the three response criteria. In various embodiments, patients are also tested to ensure that they do not have uncontrolled infection, sepsis, or septic shock prior to using terlipressin to treat HRS-1 patients.

In various embodiments, the terlipressin dose is given as a continuous IV feed.

In one or more embodiments, the terlipressin dose is 1 mg administered intravenously every 6 hours as a slow bolus injection over 2 minutes.

In various embodiments, the terlipressin dose is not given as a bolus.

Terlipressin may be administered to patients for up to four days, where patients may be tested daily for four days to determine whether the patient is responding to terlipressin treatment. In various embodiments, response to terlipressin treatment may be indicated by a change in the patient's serum creatinine level, where the indication may be a decrease in SCr of at least 25% from baseline. In various embodiments, terlipressin can be administered for at least 4 days.

At 260 , the change in serum creatinine is measured after 4 days of terlipressin treatment, and if the serum creatinine level improves, terlipressin treatment is continued. In various embodiments, a sufficient improvement in serum creatinine levels after 4 days of treatment is indicated by a decrease in serum creatinine levels of at least 1.0 mg/dL, or a decrease in serum creatinine levels of about 1.7 mg/dL.

In various embodiments, if improvement is seen over the previous 1 to 4 days, the patient receives terlipressin for an additional 3 to 8 days. In various embodiments, if improvement is seen over the previous 1 to 4 days, the patient receives terlipressin for an additional 3 to 4 days.

In various embodiments, if the patient exhibits a decrease in serum creatinine levels, terlipressin administration to the patient is continued for an additional 3 to 12 days beyond the initial 4 days. In various embodiments, terlipressin administration to the patient may be continued until at least one SCr value <1.5 mg/dL is obtained. In various embodiments, the duration of treatment may be extended up to 15 or 16 days if HRS reversal is first achieved on day 13 or 14, respectively. In various embodiments, the duration of treatment of a patient with terlipressin can be from 1 to 28 days. In various embodiments, a decrease in serum creatinine level can be indicated by a decrease in SCr from baseline of at least 1% or at least 5% or at least 10% or at least 15% or at least 20% or at least 25%.

In one or more embodiments, the patient may have received albumin prior to starting the terlipressin treatment protocol and/or prior to determining that the patient has HRS-1, which is at least two of the three response criteria. In various embodiments, albumin may be administered to the patient 7 to 2 days prior to starting terlipressin administration to the patient. In various embodiments, albumin treatment includes administering to the patient 1 g of albumin per kg of body weight up to 100 g of albumin per day. In various embodiments, albumin may be administered in a range of about 20 g/day to about 50 g/day, wherein albumin may be administered during the period of time that terlipressin is administered to the patient.

A non-limiting embodiment of a method of treating a patient with HRS-1 who exhibits at least 2 of the 3 response criteria with terlipressin includes administering to the patient in need of such treatment a terlipressin dose of 2.0 to 2.0 to 2.0 to 2.0 to 2.0 per day per day for 1 to 28 days. 12.0 mg range, or 2.0 to 4.0 mg per day for 1 to 7 days, wherein the dose may be administered by continuous IV feeding or slow bolus injection.

Embodiments of the present disclosure also relate to treating patients with HRS-1 and meeting two or more response criteria using one dose of terlipressin every 6 hours, wherein the dose achieves reversal of HRS-1. It ranges from about 0.5 mg to 2.0 mg for 3 to 8 days.

Embodiments of the present disclosure also provide for initiating terlipressin treatment within 48 hours after determining that the patient exhibits HRS-1 and at least two of the three response criteria but does not have sepsis, septic shock, or uncontrolled infection. It's about doing.

Another aspect of the disclosure relates to a method of dispensing a pharmaceutical product.

In one or more embodiments, the method of dispensing includes supplying terlipressin to a healthcare provider, who may be responsible for treating a patient suffering from type 1 hepatorenal syndrome. In various embodiments, the patient does not have overt sepsis, septic shock, or uncontrolled infection. In various embodiments, the method comprises treating a patient suffering from type 1 hepatorenal syndrome in the absence of overt sepsis, septic shock, or uncontrolled infection with an amount of terlipressin effective in reducing SCr (1) 4,000 cells/mm ³ Patients with at least 2 of the following: white blood cell count (WBC) less than or greater than 12,000 cells/mm ³ , (2) heart rate greater than 90 beats per minute (BPM), or (3) HCO ₃ <21 mmol/L Includes providing recommendations to health care providers to treat. In one or more embodiments, the healthcare provider follows the recommendations and determines that the patient is suffering from HRS-1 but is not in overt sepsis, septic shock, or uncontrolled infection and is treated with (1) 4,000 doses of terlipressin effective to reduce SCr. At least two of the following: (2) white blood cell count (WBC) less than 12,000 cells/mm ³ or greater than 12,000 cells/mm ³ , (2) heart rate greater than 90 beats per minute (BPM), or (3) HCO ₃ <21 mmol/L Treatment is administered to patients with

The efficacy of terlipressin compared to placebo in achieving proven HRS-1 reversal may be more pronounced in subgroups of patients with systemic inflammatory response syndrome (SIRS). Inflammatory cytokines have been implicated in the pathogenesis of HRS-1. Without being limited by any one theory, terlipressin reduces the extent of bacterial translocation across the digestive tract wall in patients with decompensated cirrhosis through its ability to reduce portal pressure, ultimately reducing endotoxemia and promoting pro-inflammatory cytokine production. terlipressin, and thus patients may respond more easily to the hemodynamic effects of terlipressin.

Figure 3 shows unexpected results produced by an exemplary treatment protocol.

Aspects of the present disclosure relate to methods of treating and/or reversing HRS-1. As shown in Figure 4, an exemplary embodiment of a method of treating an adult patient with HRS-1 via an embodiment of the terlipressin treatment protocol.

In various embodiments, patients initially identified as having end-stage liver disease for whom treatment with a vasodilator may provide improvement in kidney function may be tested to determine the extent of the patient's cirrhosis and renal failure. In an embodiment, the patient to be treated is an adult patient diagnosed with HRS-1.

In one or more embodiments, a method of treating an adult patient with hepatorenal syndrome type 1 (HRS-1) comprises assessing baseline serum creatinine (SCr) levels prior to administering terlipressin to the patient, IV for 1 to 3 days. starting to administer to the patient about 0.5 mg to about 1 mg of terlipressin every 6 hours, and assessing the patient's serum creatinine level at day 4 ± 1 from the start of administration; and administering a modified terlipressin dose based on a comparison of the baseline serum creatinine level with the serum creatinine level assessed on day 4 ± 1. In some embodiments, the method is administered twice, at least 2 hours apart, for up to 14 days. It may further include continuing administration until 24 hours after a continuous serum creatinine level of 1.5 mg/dL.

In one or more embodiments, the terlipressin dosage is about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, or 0.5 mg to about 5.0 mg, or 0.5 mg to about 2.0 mg, or 0.5 mg per single dose. It may range from about 1.0 mg, about 0.85 mg to about 1.7 mg, or about 1.0 mg to about 2.0 mg.

In one embodiment, the administered terlipressin may be terlipressin acetate. Terlipressin acetate dosages may be administered to patients in the range of about 0.5 mg to about 2.0 mg. In various examples, the terlipressin acetate dosage may be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg.

Terlipressin can be prepared for injection as a white to off-white lyophilized powder in single-dose vials to be reconstituted in a dose of 0.85 mg of terlipressin (equivalent to 1 mg of terlipressin acetate). In some embodiments, the terlipressin acetate dosage may be given as an initial dose of about 0.5 mg or about 1 mg. In at least one example, administration may begin with 1 mg of terlipressin acetate. In other embodiments, the terlipressin dosage may be changed after a period of time after administering the initial dose. In at least one example, the modified dosage may be about 2 mg of terlipressin acetate.

In various embodiments, the injectable agent may be administered intravenously as a slow bolus injection over 2 minutes, where the dose may be repeated every 4 to 6 hours. In one or more embodiments, the injectable agent may be administered to the patient as an IV drip over a period of about 4 hours to about 6 hours.

In an example, the initial terlipressin dose ranges from about 0.5 mg to about 1.0 mg and is administered to the patient in a series of single doses every 4 to 6 hours, such that the patient receives a single dose of terlipressin ranging from about 0.5 mg to about 1.0 mg. After receiving your dose, receive another single dose 4 to 6 hours later. In various embodiments, a patient may receive 4 to 6 doses over a 24-hour period, where each dose ranges from about 0.5 mg to about 1.0 mg. In various embodiments, the total dose does not exceed 4.0 mg over a 24-hour period. In some examples, the terlipressin dosage may be about 0.85 mg or about 1.0 mg of terlipressin acetate.

At step 410 , in some embodiments, baseline serum creatinine levels may be measured prior to terlipressin administration on Day 1. Patients with HRS-1 can then be administered an initial dose of terlipressin. In an example, the initial terlipressin dose may be about 0.5 mg to about 1.0 mg, administered every 6 hours for about 1 to 3 days. In at least one example, the initial dose may be about 1.0 mg of terlipressin acetate (i.e., 0.85 mg of terlipressin).

At step 420 , on day 4 ± 1 of administration (e.g., after at least 10 doses), serum creatinine levels may be assessed and compared to baseline levels. In various embodiments, patients administered terlipressin are evaluated at least once during days 1 to 4 ± 1 of administration to determine whether the patient responds to terlipressin. In various embodiments, patients may be tested once at the end of the third or fourth day of terlipressin administration. In some instances, serum creatinine levels can be assessed continuously (e.g., daily) until administration is discontinued. In various embodiments, the dosage administered to the patient can be adjusted based on the measured serum creatinine level(s). In various embodiments, patients administered terlipressin can have their serum creatinine levels monitored for the entire period the patient is receiving terlipressin. In one or more embodiments, the patient's serum creatinine level can be tested daily, every other day, every two days, or every three days to determine whether the patient is still responding positively to terlipressin treatment.

Serum creatinine levels can be measured by any method known in the art, such as the Jaffe reaction using alkaline picrate. GFR can be tracked by scavenging capacity studies of exogenous markers such as inulin, iohexol, iopalumate, and Cr51-EDTA, or by creatinine testing by reference methods based on isotope dilution-mass spectrometry (IDMS). It can be measured directly by estimated glomerular filtration rate (eGFR) using the method.

In various embodiments, the patient's creatinine level determines whether the patient's serum creatinine has decreased and is greater than or equal to about 1.0 mg/dL from the patient's initial baseline value, or in the range of about 1.0 mg/dL to about 2.0 mg/dL. A decrease in level, or about 1.7 mg/dL, indicates an improvement in kidney function and is evaluated to determine if the patient is responding to terlipressin. In some examples, the assessed serum creatinine level can be at least 30% lower than the baseline serum creatinine level, between 1% and 29% lower than the baseline serum creatinine level, or at least 0% below the baseline serum creatinine level. In steps 430 , 440 and 450 , modified terlipressin doses may be administered based on a comparison of the baseline serum creatinine level with the assessed serum creatinine level at Day 4 ± 1.

At step 430 , if the assessed SCr level has decreased by at least 30% from the baseline SCr level on Day 4 ± 1, the patient may continue to be administered terlipressin at a dose of about 0.5 mg to about 1.0 mg every 6 hours. For example, if the assessed SCr level decreases by more than 30% from the baseline SCr level, the modified dose may be the same as the initial dose (e.g., 0.5 mg to 1.0 mg).

At step 440 , if the assessed SCr level has decreased but is less than 30% below the baseline level by day 4 ± 1, the terlipressin dose may be increased from about 1.0 mg to about 2.0 mg every 6 hours. For example, if the assessed SCr level has decreased by less than 30% from the baseline level, the modified dosage may be about 0.1 mg to about 2.0 mg of terlipressin every 6 hours (±30 minutes) (8 mg/day). In at least one example, the altered dose may be. If the subject has coronary artery disease; Alternatively, in clinical settings of circulatory overload, pulmonary edema, or refractory bronchospasm, the evaluation dose cannot be increased from the initial dose. In various embodiments, if dosing is interrupted due to non-ischemic adverse events, terlipressin can be resumed at the same or lower dose (i.e., 0.5 to 1 mg q6h).

At step 450 , if the assessed SCr level is above the baseline SCr level on Day 4 ± 1, terlipressin administration may be discontinued. For example, a modified dose could be to discontinue terlipressin administration if the assessed SCr level is above the baseline SCr level.

In step 460 , terlipressin administration is administered to the patient at least 2 hours apart or for up to 14 days. This may continue until 24 hours after reaching a secondary serial serum creatinine value of 1.5 mg/dL. In various embodiments, the dosage may be repeated every 4 to 6 hours for a period of 1 day or more until the patient shows recovery, or until the patient shows no further improvement. In various embodiments, the duration of treatment of a patient with terlipressin can be 1 to 14 days. In various embodiments, terlipressin can be administered for at least 4 days. In various embodiments, the patient is administered terlipressin for up to 14 days, unless the patient experiences an adverse event. In various embodiments, terlipressin is administered for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least It may be administered for 13 days, or at least 14 days. In some examples, terlipressin may be administered to a patient for a period of time ranging from about 2 days to about 14 days, or for a period of time ranging from about 4 days to about 8 days. In various embodiments, the period of time ranges from about 7 days. In various embodiments, terlipressin treatment may be continued until there is a complete response.

In one or more embodiments, a treatment protocol comprising a terlipressin dose surprisingly provides reversal of one or more complicating factors, such as vasodilation, and reduces mortality due to associated complications within a 90-day window of starting treatment.

The patient's treatment may include improving kidney function. Improvement in kidney function is achieved by at least a 25% or 30% reduction in SCr from baseline and reversal of HRS (when SCr levels are defined as a decrease to 1.5 mg/dl) and/or verified HRS reversal (at least 48 hours apart). defined as two serum creatinine values of 1.5 mg/dL).

In one or more embodiments, the patient is alive 90 days after initiation of terlipressin treatment. For example, patients who experience HRS reversal, assayed HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin have at least a 60%, 65%, or 70% chance of survival at 90 days. You can. In another embodiment, the patient is alive 90 days after liver transplantation following initiation of terlipressin treatment. For example, patients who experience HRS reversal, assayed HRS reversal, and/or greater than 30% improvement in SCr after receiving terlipressin have at least a 35%, 40%, or 45% chance of survival at 90 days. It can be.

In various embodiments, the HRS-1 adult patient is also SIRS positive. In one or more embodiments, patients with uncontrolled infection, sepsis, or septic shock are excluded from terlipressin treatment.

In one or more embodiments, the patient also consumes up to 100 g/day of albumin each day the patient is treated with terlipressin. In some instances, albumin may be continued to be administered to the patient even after terlipressin has been discontinued.

The percentage of patients who can achieve proven HRS reversal may be significantly higher with terlipressin than with placebo. In some instances, patients administered terlipressin are treated at least 2 hours apart during treatment or discharge until day 14. Two consecutive SCr values of 1.5 mg/dl can be achieved. This demonstrates a robust and clinically meaningful improvement in kidney function. In a further example, patients administered terlipressin are able to discontinue renal replacement therapy (RRT) for at least 10 days, highlighting the durability of these improvements in renal function. The durability of HRS reversal with terlipressin may last at least up to 30 days without the need for RRT. In another example, patients administered terlipressin can achieve survival for at least 10 days, establishing treatment effectiveness on the key clinical outcome of early survival. Terlipressin may be superior to placebo in inducing responses across all levels of baseline SCr, and the response rate to terlipressin is inversely related to baseline SCr.

Renal replacement therapy poses special challenges to patients with HRS-1 and advanced chronic-to-acute liver failure, and the lower RRT rates and longer RRT-free survival in the terlipressin group are clinically relevant. The significant reduction in the need for RRT extending into the post-transplant period in the terlipressin group has important clinical implications because post-transplant RRT is an important predictor of post-transplant morbidity, including poorer graft survival mortality and resource utilization. .

In a further aspect of the disclosure, a method of increasing survival of patients with HRS-1 and low MAP comprises administering an effective terlipressin dose about every 6 hours by intravenous (IV) bolus injection over about 2 minutes. and administering to a patient in need, wherein the dose is sufficient to increase MAP and decrease heart rate of the patient.

In another aspect of the disclosure, a method of increasing survival of HRS-1 patients includes administering an effective dose of terlipressin to a patient in need of an effective terlipressin dose approximately every 6 hours by intravenous (IV) bolus injection over approximately 2 minutes. and administering, wherein the dose is sufficient to increase the patient's diastolic, systolic and MAP and decrease heart rate. In a further aspect of the disclosure, a method of increasing survival of HRS-1 patients includes administering a dose of about 0.5 mg to about 2 mg every about 4 to 10 hours by intravenous (IV) bolus injection over about 1 to 5 minutes. A method comprising administering to a patient in need an effective dose of terlipressin acetate, wherein the dose is sufficient to increase MAP and decrease heart rate of the patient.

Terlipressin may cause adverse effects generally consistent with its mechanism of action (MOA) and class of effects, with the potential for an increased risk of certain serious adverse events. Patient selection is very important when using terlipressin. Efficacy and safety outcomes in patients with serum creatinine ≥ 5 mg/dL and/or Model End Stage Liver Disease (MELD) score ≥ 35 upon terlipressin initiation may represent a turning point in clinical outcomes. For example, SCr ≥ 5 mg/dL, MELD score ≥ 35, and/or chronic acute liver failure (ACLF) grade ≥ 3 may be the threshold for presenting with advanced disease, decreased renal function response, and increased adverse events. Clinicians may consider avoiding terlipressin in late-onset HRS-1 or advanced chronic-to-acute liver failure, as the potential for benefit is low. The use of terlipressin in patients with SCr ≥ 5 mg/dL may be considered only if the expected benefits to the patient outweigh the potential risks. In another embodiment, the use of terlipressin in patients with at least about SCr > 5 mg/dL may be considered only if the expected benefit to the patient outweighs the potential risk. Adverse events may include ischemic or respiratory symptoms that may result in serious or fatal outcomes. For example, one possible respiratory symptom is severe respiratory failure, which could be a major safety concern. In one embodiment, the risk of respiratory failure may not be reliably predicted and managed. Respiratory failure can have several causes. Other adverse events may include ischemia, pneumonia, or sepsis without a clear mechanism. The clinical presentation and management of the reaction can be complicated by the risk of fluid overload and associated albumin usage.

Management of adverse events, side effects, and undesirable symptoms for the present invention may include a variety of palliative strategies. In one embodiment, the methods of the invention include palliative strategies that actively manage fluid overload during therapy. Active management of fluid overload may include reducing or discontinuing albumin, administration of other fluids, and/or cautious use of diuretics. For clarity, reducing albumin administration may include lowering the dose or blocking administration of albumin. If fluid overload persists, treatment methods may further include reducing or discontinuing terlipressin treatment. Managing fluid overload by reducing or discontinuing albumin, other fluid administration, and/or cautious use of diuretics may also occur, and the patient may develop respiratory failure, severe renal disease, pulmonary edema, dyspnea, tachypnea, ischemia, or the like. It additionally has a combination of .

For example, if symptoms persist, active management of fluid overload may include changing the dose of terlipressin. If symptoms, side effects, or adverse events persist, aggressive management of fluid overload may include terlipressin dose reduction, dose interruption, or discontinuation (i.e., discontinuation of treatment). In another embodiment, the methods of the invention include a palliative strategy that monitors oxygen saturation during therapy. Monitoring oxygen saturation through pulse oximetry can identify patients at risk for serious adverse respiratory events.

Patients with chronic acute liver failure (ACLF) grade ≧3 and/or serum creatinine ≧5 mg/dl treated in accordance with the presently claimed invention may be at significant risk of serious or fatal respiratory failure. In one embodiment, the palliative strategy may be to stop or discontinue treatment in patients with serum creatinine > 5 mg/dl or ACLF grade > 3. Another palliative strategy of the present invention is to stop or discontinue treatment in patients with a hepatic encephalopathy score ≥ 3. Another palliative strategy for use in the present invention is to exclude patients from treatment (i.e., exclusion criteria) with serum creatinine ≥ 5 mg/dl or hepatic encephalopathy score ≥ 3 and/or ACLF grade ≥ 3. Stated differently, the invention also includes embodiments (i.e., inclusion criteria) in which patients are only treated if serum creatinine <5 mg/dl, hepatic encephalopathy score <3, and/or ACLF grade <3. In some embodiments, terlipressin may be administered to patients whose serum creatinine is at or below a critical level. In some examples, the threshold or threshold level may be about 5 mg/dl. In at least one example, terlipressin may be administered to a patient if the patient's serum creatinine level is <5 mg/dl.

In some embodiments, the duration of terlipressin treatment is for patients exhibiting SCr ≥ 5 mg/dL and SCr < 5 mg/dL compared to about 6 days to about 11 days for patients treated with terlipressin. In this case, it may be about 6 to about 7 days. The proportion of patients receiving antibiotics or albumin may not differ significantly between groups.

In a further embodiment, patients who have a serum creatinine level of less than 5 mg/dl and who are administered a terlipressin dose have a reduced likelihood of adverse events, overall, compared to patients who have a serum creatinine level of 5 mg/dl or more and who are administered terlipressin. may have increased survival, decreased overall ICU, non-ICU, or hospital admissions, increased likelihood of complete response, and/or increased likelihood of partial response. A complete response indicates that the patient's SCr level is It may have decreased to 1.5 mg/dl. In some instances, the patient's serum creatinine level is Terlipressin may be continued to be administered to the patient until the level is 1.5 mg/dl. In another example, terlipressin is measured in two consecutive measurements at least 2 hours apart. Administration may continue to patients until 24 hours after a SCr level of 1.5 mg/dl. A partial response may be when the patient's SCr level is reduced by ≥ 20%, preferably ≥ 30%, but > 1.5 mg/dL. For example, terlipressin may be continued to be administered to a patient until the patient's serum creatinine level improves by greater than 20%.

Higher presentation SCr may be associated with poorer efficacy in HRS-1 patients. For example, patients with a SCr ≥ 5 mg/dL may be significantly more likely to experience adverse events when receiving terlipressin than patients with a presenting SCr < 5 mg/dL. In some instances, complete relapse occurs in about 50% to about 60% of patients with a presenting SCr <5 mg/dL compared to about 10% to about 20% of patients with a presenting SCr ≥ 5 mg/dL upon terlipressin administration. reaction can be achieved. In another example, in about 15% to about 25% of patients with a presenting SCr <5 mg/dL compared to about 10% to about 20% of patients with a presenting SCr ≥ 5 mg/dL upon terlipressin administration. reaction can be achieved. In a further example, patients with a presenting SCr ≥ 5 mg/dL have fluid overload compared to patients with a SCr < 5 mg/dL (about 10% to about 20% and about 5% to about 10%, respectively) upon terlipressin administration. Alternatively, pulmonary edema (about 20% to about 30%) and multi-organ failure (about 25% to about 35%) may be more likely to occur. Overall survival may be significantly better in patients with a presenting SCr < 5 mg/dL than in patients with a presenting SCr ≥ 5 mg/dL when receiving terlipressin. In a further example, patients with SCr <5 may have a significantly shorter ICU stay of about 0.5 to about 1.5 days compared to about 5 to about 10 days for patients with a presenting SCr > 5 mg/dL when administered terlipressin. there is. In yet a further example, patients with SCr <5 have significantly shorter non-ICU hospitalizations of about 20 to about 25 days compared to about 30 days to about 40 days for patients with presenting SCr > 5 mg/dL when administered terlipressin. You can have a period of time. In a further example, patients with SCr <5 have a significantly shorter hospital stay of about 20 to about 25 days compared to about 40 days to about 45 days for patients with presenting SCr ≥ 5 mg/dL when administered terlipressin. You can have a total period.

An additional palliative strategy of the present invention is to stabilize patients with respiratory reactions. Among other factors, the invention may further include managing fluid overload and pneumonia prior to treatment. Mitigation strategies that may be used as part of the present invention may result in reduced adverse events, reduced risk of death, reduced incidence of death, and combinations thereof. Reducing the risk of death or reducing the incidence of death may include overall survival (e.g., measured as alive at 90 days after starting treatment).

Higher baseline MELD scores may be linked to poorer efficacy (e.g., poor survival) in HRS-1 patients. For example, patients with a baseline MELD score greater than 35 may be significantly more likely to experience an adverse event when administered terlipressin than patients with a baseline MELD score less than 35. If a patient is listed for liver transplant with a MELD score ≥35, the patient may be excluded from treatment.

In some embodiments, provided herein are methods of treating a HRS-1 patient by administering a terlipressin dose to the patient by IV injection when the patient has a baseline Model End Stage Liver Disease (MELD) score of less than 35. . In some instances, the patient is listed for transplant at baseline and has a baseline MELD <35. In another example, the patient is not listed for transplant at baseline and has a MELD score <35 or ≥35. Administration of terlipressin to this subset of patients may increase the patient's overall survival, decrease the patient's overall ICU or hospital admissions, increase the patient's complete response, and/or increase the patient's partial response. In some embodiments, the overall survival rate at 90 days for patients with a baseline MELD score <35 treated with terlipressin is between about 5% and 5% compared to patients with a baseline MELD score ≥35 treated with placebo and/or terlipressin. It can be increased by up to 50%, about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50%. . In some embodiments, the 90-day transplant-free survival rate for patients with a baseline MELD score <35 treated with terlipressin is about 5% compared to patients with a baseline MELD score ≥35 treated with placebo and/or terlipressin. to 50%, about 5% to 15%, about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50%. there is.

In some embodiments, patients with a MELD score of less than 35 may also have severe kidney disease, pulmonary edema, dyspnea, or a combination thereof.

The method includes obtaining the patient's baseline MELD score, obtaining the patient's serum creatinine (SCr) level prior to administering a terlipressin dose to determine the baseline SCr level, and/or the patient's chronic moderate-acute liver failure. (ACLF) grade. In some embodiments, terlipressin may not be administered if the baseline SCr is ≧5 mg/dl and/or the ACLF grade is ≧3. In other embodiments, the method may include discontinuing administration or reducing the dose of terlipressin in patients with SCr ≥ 5 mg/dl and/or ACLF grade ≥ 3. In a further embodiment, a terlipressin dose may be administered to a patient if the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg/dl. Patients with a baseline MELD score less than 35 may be further monitored for SCr levels greater than 5 mg/dl or ACLF grade 3 or greater for terlipressin discontinuation. In some instances, the patient is listed for transplant at baseline and has a baseline MELD <35. In another example, the patient is not listed for transplant at baseline and has a MELD score <35 or ≥35.

In some embodiments, administering terlipressin to a patient with a baseline MELD score <35 may reduce the patient's risk of death (i.e., may increase survival). Patients can be listed for transplant and have a MELD score <35. In one embodiment, treating a patient on the transplant list at baseline with a baseline MELD score <35 may further help avoid compromising the patient's position on the transplant list. In some embodiments, a patient may have a reduced risk of having the patient's place on the transplant list impaired or affected by administration of terlipressin.

Only patients actively listed for transplant can receive an available organ. The waiting time to receive a liver transplant depends on other factors (e.g. MELD score, geographic region, blood type) and can range from a few days to several months depending on the MELD score. Excluding patients who are likely to receive a transplant during or shortly after treatment with terlipressin will reduce the risk that such patients will not receive a transplant due to any adverse effects of terlipressin therapy, such as respiratory failure. You can. It also prioritizes patients at highest risk of death while waiting for a liver, ensuring livers are available to those who need them most.

For example, patients with a MELD score ≥ 35 may be higher on the transplant list, so waiting for a liver transplant may result in a faster cure time than treatment with terlipressin. Therefore, not treating a patient listed for liver transplant with a baseline MELD score ≥ 35 may allow the patient to maintain their spot on the transplant list and receive a transplant sooner than if they were initially treated with terlipressin. In at least one embodiment, a patient may be treated only if the patient belongs to a patient population with a median wait time from listing to transplant of at least about 5.6 months. In another embodiment, a patient may be excluded from treatment if the patient belongs to a patient population with a median wait time from enumeration to transplant of 0.23 months (approximately 7 days) or less. In a further embodiment, the patient's total duration of ICU hospitalization, non-ICU hospitalization, and/or hospital hospitalization is defined as having a baseline MELD score <35, a baseline SCr level of <5 mg/dl, and/or a SCLF grade of <3. It may be shortened depending on the patient.

In some embodiments, terlipressin administration is continued until there is a complete or partial response. In some embodiments, discontinuing or reducing the dose of terlipressin occurs in patients with respiratory failure. For example, administering terlipressin to patients with a baseline MELD score <35 may reduce the patient's likelihood of developing respiratory failure compared to patients with a baseline MELD score ≥35.

The terlipressin dose administered may be 0.5 mg to about 2 mg terlipressin acetate and may be administered by IV bolus injection over about 1 to 5 minutes every 4 to 10 hours. In at least one example, terlipressin may be administered every 6 hours as an IV bolus injection over 2 minutes.

In some embodiments, the method may further include monitoring oxygen saturation of the patient during treatment with terlipressin. Monitoring oxygen saturation may reduce the incidence of adverse events. For example, a method of treating a patient with HRS includes obtaining a baseline oxygenation level (SpO ₂ ) via pulse oximetry and, if the patient is not suffering from hypoxia, administering a dose of terlipressin to the patient by IV injection. , and monitoring the patient's SpO ₂ during treatment with terlipressin. The patient's SpO ₂ can be obtained at baseline before the first dose of terlipressin, followed by at least 3 times per day, at least 4 times per day, at least 5 times per day, at least 6 times per day, or terlipressin administration. It can be monitored continuously throughout the period. The patient's oxygen saturation (SpO ₂ ) may be monitored for hypoxia; an SpO ₂ value of <90% may indicate some degree of hypoxia. Fraction of inspired oxygen (FiO ₂ ) can also be monitored as a sign of lung function. For example, FiO ₂ ≥ 0.36 may be a sign of impaired lung function. In one embodiment, the method may further include discontinuing administration or reducing the terlipressin dose if hypoxia is detected.

In a further embodiment, the method may further comprise monitoring the patient for fluid overload during treatment with terlipressin. The terlipressin dose can then be reduced or discontinued if fluid overload occurs. If fluid overload occurs, the patient may be given diuretics.

In one embodiment, the method may further include measuring the patient's SCr level during administration of terlipressin. Subsequently, the patient's SCr level was Dosing may be continued until 1.5 mg/dl or until the patient experiences a greater than 20% improvement in SCr. In some instances, administration is continued until the patient experiences a greater than 30% improvement in serum creatinine.

Additionally, to reduce the risk selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof, the population of patients eligible for treatment is reduced to a palliation group and then a dose of terripressin is administered to patients in the palliation group by IV injection. Methods of treating patients with HRS-1 are provided herein. The palliation population excludes patients with baseline ACLF grade 3, baseline serum creatinine ≥ 5 mg/dL, and/or patients on the transplant list at baseline with baseline MELD ≥ 35. . It was surprising that this remission group had improved survival, lower incidence of respiratory failure, and lower pretransplant mortality compared to the overall population treated with terlipressin. Treatment of HRS-1 patients with baseline ACLF grade 0-2, baseline SCr <5 mg/dL, and/or listed for transplant at baseline with baseline MELD <35 may have a beneficial impact on liver transplant incidence and liver transplantation. It may minimize the risk that patients listed for will not receive a transplant due to the potential adverse effects of terlipressin.

Treating these subsets of HRS patients (e.g., remission populations) results in higher rates of proven HRS reversal, lower rates of renal replacement therapy (RRT), and favorable RRT-free survival with terlipressin compared with placebo. . For example, this subset of treated patients may have reduced risks compared to the overall population, including lower incidence of respiratory failure, overall mortality, and pretransplant mortality. In some embodiments, overall survival to day 30 of patients in a remission population treated with terlipressin, verified HRS reversal, HRS reversal, persistence of HRS reversal, HRS reversal in a SIRS subgroup, and/or HRS relapse. Verified HRS reversal was approximately 5% to 15%, approximately 10% to 20%, approximately 25% to 35%, or approximately 30% to 40% compared to the overall population treated with terlipressin. It can be increased by 5% to 50%. In another embodiment, overall survival to day 30 of patients in a remission population treated with terlipressin, verified HRS reversal, HRS reversal, persistence of HRS reversal, HRS reversal in a SIRS subgroup, and/or HRS relapse. Verified HRS reversal was approximately 5% to 15%, approximately 10% to 20%, approximately 25% to 35%, approximately 30% to 40%, approximately 35% to 45%, compared to the overall population or the remission group receiving placebo. %, about 5% to about 5%, including about 40% to 50%, about 50% to 60%, about 60% to 70%, about 70% to 80%, about 80% to 90%, or 90% to 100%. It can be increased up to 100%. In a further embodiment, the incidence of RRT in patients surviving to day 90 in the remission population treated with terlipressin compared to the overall population or the remission population receiving placebo is about 5% to 50%, about 5% to 15%, It may be an increase of about 10% to 20%, about 25% to 35%, about 30% to 40%, about 35% to 45%, or about 40% to 50%. In various embodiments, patients in the remission population treated with terlipressin may have an increased likelihood of survival without RRT by day 14, 30, or 60 compared to patients in the overall population treated with terlipressin. For example, patients in the remission population treated with terlipressin have a chance of surviving without RRT by about 2% to about 20% by day 14, 30, or 60 compared to patients in the overall population treated with terlipressin. %, about 5% to 15%, or about 10% to 20%. In a further embodiment, patients in the remission population treated with terlipressin are without RRT by day 14, 30, 60, or 90 compared to the overall population treated with placebo or the patients in the remission population treated with placebo. Chances of survival may increase. For example, patients in the remission group treated with terlipressin had approximately a 2 percent chance of survival without RRT by day 14, 30, or 60 compared to patients in the overall group treated with placebo or patients in the remission group treated with placebo. % to about 40%, about 5% to 10%, about 10% to 20%, about 20% to 30%, or about 30% to 40%.

Example

Example 1:

A randomized, placebo-controlled, double-blind study (“REVERSE”) was conducted to evaluate the efficacy of terlipressin for HRS type 1. The aim of the study was to determine the efficacy and safety of intravenous terlipressin compared with placebo in the treatment of adult patients with HRS type 1 receiving intravenous albumin. Cirrhosis, ascites, and 2007 International Club of Ascites (ICA) diagnostic criteria (Salerno F, Gerbes A, Gines P, Wong F, Arroyo V., Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Gut. 2007; 56:1310- Men and women aged 18 years or older with a diagnosis of HRS type 1 according to 1318) were eligible to participate. Patients with SCr levels > 2.5 mg/dL and either doubling of SCr within 2 weeks or changes in SCr levels over time showing a trajectory with a slope equal to or greater than doubling within 2 weeks were enrolled.

Exclusion criteria are intended to generate a patient sample limited to those who have functional renal impairment comparable to cirrhosis and ascites, who can safely administer terlipressin, and who are expected to survive the active study period. Among the original exclusion criteria were those for patients with systemic inflammatory response syndrome (SIRS), defined as the presence of two or more of the following findings: (1) temperature >38°C or <36°C; (2) heart rate >90/min; (3) respiratory rate > 20/min or PaCO ₂ < 32 mm Hg; (4) White blood cell count >12,000 cells/μL or <4,000/g L. This was based on concerns about enrolling patients with uncontrolled infections. However, it has been recognized that patients with decompensated liver disease often have SIRS criteria even without uncontrolled infection or sepsis, and that the presence of two or more SIRS criteria has a poor prognosis (Thabut, et al., "Model for End- Stage Liver Disease Score and Systemic Inflammatory Response Are Major Prognostic Factors in Patients with Cirrhosis and Acute Functional Renal Failure," HEPATOLOGY, Vol. 46, No. 6, December 2007, pp. 1872-1882). Moreover, the IAC criteria for defining HRS type 1 allow patients with progressive bacterial infection rather than sepsis or uncontrolled infection to be considered as HRS type 1 (as opposed to infection-related renal dysfunction) (Salerno F, Gerbes A, Gines P, Wong F, Arroyo V., Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Gut. 2007; 56:1310-1318). The trial protocol required 2 days of anti-infective therapy for documented or suspected infection and allowed enrollment for any SIRS criteria considered most likely to be explained by underlying hepatic decompensation or other non-infectious clinical circumstances. . Patients with overt sepsis, septic shock, or uncontrolled infection were excluded. This approach was felt to minimize the opportunity to enroll patients at high risk for serious infection without unduly limiting enrollment of HRS type 1 patients.

Patients selected for treatment clinically met criteria for HRS type 1, where the ICA criteria for HRS type 1 define patients with progressive bacterial infection other than sepsis as HRS type 1, as opposed to kidney dysfunction associated with infection. allowed to be considered. A diagnosis of HRS was not made if the patient showed obvious signs of uncontrolled infection despite antibiotic treatment.

During the active study period, treatment with blinded study drug continued until at least two SCr values <1.5 mg/dL were obtained at least 48 hours apart or up to 14 days apart. If HRS reversal is first achieved on day 13 or 14, respectively, the duration of treatment may be extended up to 15 or 16 days. Patients in the active treatment group received terlipressin 1 mg intravenously every 6 hours as a slow bolus injection over 2 minutes. During the active study period, criteria were provided for dose escalation, study discontinuation, treatment resumption, and treatment completion. The dosing regimen for patients in the placebo (6 mL lyophilized mannitol solution) group was identical to the terlipressin regimen. The follow-up period began after completion of study treatment and was completed 90 days after start of study treatment. Survival, renal replacement therapy, and transplantation were evaluated.

The SIRS subgroup of patients in this study was defined as any subject with ≥2 of the 3 criteria available from the research database, including: (1) WBC <4 or >12 cells/μL; (2) HR > 90 bpm and (3) HCO ₃ < 21 mmol/L. The latter criterion represents an approximation of the SIRS criterion PaCO ₂ of <32 mmHg. This approximation was derived from the HCO ₃ observed in HRS patients for whom PaCO ₂ values were available and the HCO ₃ calculated in subjects with decompensated liver disease and PaCO ₂ less than 32 mmHg. The non-SIRS subgroup was defined as subjects with the criteria <2 described above. Terlipressin response was analyzed in SIRS and non-SIRS subgroups to determine whether SIRS status affected terlipressin efficacy.

A total of 196 patients were enrolled in the study. Of the 196 patients enrolled, 58 were initially identified as having ≥2 SIRS criteria, including WBC <4 or >12 cells/μL, HR >90 bpm, and _HCO3 <21 mmol/L, where this population was identified as a SIRS subgroup. Based on the criteria defining the SIRS subgroup, baseline WBC and heart rate were slightly higher and bicarbonate slightly lower in the SIRS subgroup compared to the non-SIRS and overall study populations. The analysis results are shown in Figure 3.

It has also been recognized that patients with decompensated liver disease often have SIRS criteria even without uncontrolled infection or sepsis, and that the presence of two or more SIRS criteria has a poor prognosis.

In one or more embodiments, reversal of HRS results in SCr levels Reversal of HRS, indicated and confirmed by a decrease to 1.5 mg/dL, is achieved by two SCr values at least 48 hours apart. It is defined as 1.5 mg/dL.

As shown in Figure 3, patients confirmed to have HRS-1 and at least two of the three criteria for SIRS on the terlipressin treatment protocol had a demonstrated HRS reversal compared to placebo (32.1% vs. 3.3%). , p<0.005), HRS reversal (42.9% vs. 6.7%, p<0.002), and renal function (change from baseline in SCr, mg/dL, -1.7 vs. -0.5, p<0.0001). indicated. In contrast, in the group of patients with HRS-1 and <2 SIRS criteria, proven HRS reversal vs. placebo was 14.5% vs. 17.4%, HRS reversal vs. placebo was 15.9% vs. 18.8%, and renal function change vs. Placebo was -0.8 vs -0.7 mg/dL. These results indicate that patients are more likely to have a positive response to terlipressin treatment if two or more of the SIRS criteria are present.

Additionally, in the treatment group, patients who simultaneously met two or more of the HRS-1 and SIRS criteria had a similar overall survival rate as patients who suffered from HRS-1 but did not meet two or more of the three SIRS criteria (57.1% vs. 58%). .

Example 2:

A randomized, placebo-controlled, double-blind study (“CONFIRM”) was conducted to evaluate the efficacy of terlipressin for HRS type 1. The aim of the study was to characterize the efficacy and safety of terlipressin and albumin versus albumin alone for the treatment of HRS-1 in patients with well-defined HRS-1. This study used similar inclusion and exclusion criteria as described in Example 1.

In particular, HRS-1 was defined according to the modified previous criteria outlined by the International Club of Ascites (ICA) and, for adult patients with cirrhosis and ascites, renal function (SCr for 48 hours after diuretic withdrawal and albumin fluid challenge). It was defined as a rapid deterioration in renal function to SCr ≥2.25 mg/dL with actual or expected doubling of SCr within 2 weeks without improvement (<20% decrease). Subjects were randomized 2:1 to terlipressin (1 mg IV every 6 hours) or placebo and albumin in both groups. Treatment continued until day 14 unless verified HRS reversal (VHRSR), renal replacement therapy (RRT), liver transplantation (LT), or SCr above baseline (BL) occurred on day 4. The primary endpoint, VHRSR, is measured by measuring two consecutive SCr values at least 2 hours apart. Defined as 1.5 mg/dL, subjects had second SCr alive without RRT for at least 10 days after 1.5 mg/dL; HRS reversal (HRSR) is when SCr It decreased to 1.5 mg/dL. Secondary endpoints included HRS reversal (all SCr values during treatment). 1.5 mg/dl), HRS reversal without RRT by day 30, HRS reversal in patients with systemic inflammatory response syndrome, and proven HRS reversal without relapse by day 30.

The patient was at least 18 years old, had cirrhosis, ascites, rapidly progressive renal failure, and SCr had doubled to at least 2.25 mg/dL within 14 days. Key exclusion criteria included SCr exceeding 7.0 mg/dL, one or more large-volume paracentesis greater than 4 L within 2 days of randomization, evidence of parenchymal renal disease or obstructive uropathy, or the presence of sepsis and/or uncontrolled bacterial infection. Patients with serious cardiovascular disease or recent (within 4 weeks) renal replacement therapy (RRT) were excluded.

300 subjects were enrolled in the study. Of the 300 subjects, 199 were randomized to terlipressin and 101 to placebo (albumin alone). Patients were stratified by quantifying SCr (<3.4 mg/dL or ≥3.4 mg/dL) and preenrollment high-volume paracentesis (at least one single reaction of ≥4L or <4L within 3 to 14 days prior to randomization). Patients in the terlipressin group (165 of 199; mean [SD] total dose of 199.4 [146.8] g) versus 91.1% (92 of 101; mean [SD] total dose of 239.5 [183.6] g) in the placebo group (P=0.06). SD] dose), albumin was co-administered in 82.9% of cases. 145 patients (72.9%) in the terlipressin group and 72 patients (71.3%) in the placebo group had previously received midodrine and octreotide.

Population demographic and BL clinical characteristics were similar between treatment groups. For example, the two treatment groups had similar mean age, weight, height, gender distribution, ethnic distribution, race distribution, presence of alcoholic hepatitis, baseline serum creatinine, large volume paracentesis (LVP) randomization stratum, and baseline model end-stage liver disease ( MELD) score, baseline Child-Pugh score, baseline white blood cell count, baseline bilirubin, baseline mean arterial pressure (MAP), baseline heart rate, baseline blood urea nitrogen (BUN), baseline bicarbonate ( _HCO ) or carbon dioxide ( CO ₂ ), baseline temperature, baseline respiratory rate, baseline Acute Liver Failure (ACLF) grade, baseline Chronic Liver Failure-Sepsis Organ Failure Assessment (CLIF-SOFA) score and presence of previous conditions/treatments such as esophageal variceal hemorrhage (EVH) banding, had pneumonia, urinary tract infection (UTI), spontaneous bacterial peritonitis (SBP), and albumin receipt. The proportion of patients who underwent LT in each group was 23.1% for terlipressin and 28.7% for placebo.

Baseline SCr values were assessed before patients received their assigned treatment. Patients received blinded assigned treatment (terlipressin or placebo) 1 mg administered intravenously over 2 minutes every 6 hours (±30 minutes). According to current guidelines, it is strongly recommended that all subjects be administered albumin (1 g/kg up to 100 g/day on day 1 and 20-40 g/day thereafter). If SCr decreases <30% from baseline on day 4 after at least 10 doses of study drug, 2 mg every 6 hours (±30 minutes), except in subjects with coronary artery disease or circulatory overload, pulmonary edema, or bronchospasm. The dose should be increased to (8 mg/day). Dose restart after discontinuation was permitted for adverse events, except for cardiac or mesenteric ischemia, which led to permanent discontinuation of treatment.

The primary efficacy endpoint is while alive without RRT for at least 10 days after achieving verified HRS reversal, excluding SCr values after RRT, transvenous intrahepatic portosystemic shunt, liver transplantation, or open-label vasopressors from the primary endpoint analysis. The incidence of verified HRS reversal was defined as the percentage of patients with two consecutive SCr values ≤1.5 mg/dL at least 2 hours apart. Fifty-eight patients (29.1%) treated with terlipressin achieved HRS reversal, validated against 16 patients (15.8%) treated with placebo (P=0.01).

Secondary efficacy endpoints were the incidence of HRS reversal, defined as the percentage of patients with an on-treatment SCr value of ≤1.5 mg/dL; Incidence of HRS reversal, defined as the percentage of patients with HRS reversal without RRT by day 30; Incidence of HRS reversal among patients with systemic inflammatory response syndrome; and the incidence of verified HRS reversal without HRS recurrence by day 30. 36.2% of patients treated with terlipressin achieved HRS reversal compared to 16.8% treated with placebo (P<0.001). 31.7% of patients treated with terlipressin achieved HRS reversal without RRT by day 30 compared with 15.8% of patients treated with placebo (P=0.003). The reduction in RRT requirements with terlipressin appears to extend into the post-liver transplantation period, with 9 of 46 (19.6%) patients requiring RRT after transplant compared with 13 of 29 or 44.8% in the placebo group. , (P=0.04) is significantly less than that observed. There was a slightly lower percentage of patients receiving liver transplantation (23.1% [46/199]) in the terlipressin group compared to the placebo group (28.7% [29/101]). 24.1% of patients treated with terlipressin achieved verified HRS reversal without relapse by day 30 compared to 15.8% treated with placebo (P=0.09).

132/300 (44%) of the subjects met criteria for systemic inflammatory response syndrome (SIRS) as defined in Example 1. Patients with overt sepsis, septic shock, or uncontrolled infection were excluded. In the SIRS subgroup, 84 patients were treated with terlipressin according to the protocol in Example 1, and 48 patients received albumin only (placebo).

Some baseline values for SIRS patients treated with terlipressin or placebo are shown in Table 1 below.

As shown in Table 2, 33.3% of SIRS patients treated with terlipressin experienced HRS reversal, compared to only 6.3% of SIRS patients given placebo. Among SIRS patients treated with terlipressin, 26.2% experienced verified HRS reversal compared to only 4.2% of SIRS patients given placebo.

Table 3 shows the maximum 90-day transplant freedom in subjects with HRS reversal and/or >30% improvement in serum creatinine (SCr) compared with subjects without HRS reversal and/or >30% improvement in SCr in the SIRS subgroup of the intent-to-treat population. Shows survival time. Of the SIRS subgroup treated with terlipressin that showed HRS reversal and/or at least 30% improvement in SCr, 45.5% were alive at 90 days and did not undergo transplantation compared to 28.6% with placebo. Of the SIRS subgroup treated with terlipressin that showed HRS reversal and/or at least 30% improvement in SCr, 72.7% were alive at day 90 compared to 57.1% with placebo.

In the SIRS subgroup of the intention-to-treat (ITT) population, a significantly higher proportion of subjects achieved HRS reversal in the terlipressin group (33.3%) than in the placebo group (6.3%). Among subjects with SIRS at baseline, the incidence of RRT was lower in the terlipressin group compared to the placebo group at all follow-up time points (Table 4). The mean cumulative frequency of RRT by day 90 was 7.3 days in the terlipressin group compared with 15.2 in the placebo group.

The median time to first RRT was 6.0 days in the terlipressin group and 5.5 days in the placebo group. Transplant-free survival estimates to 90 days were higher in the terlipressin group than in the placebo group for subjects with SIRS at baseline (Table 5).

Estimates of overall transplant-free survival after day 30 and through day 90 were slightly higher in the terlipressin group than in the placebo group for subjects with SIRS at baseline. For the SIRS subgroup, overall survival of subjects to day 90 was analyzed to compare differences between subjects who achieved verified HRS reversal or >30% improvement in serum creatinine and those who did not. For the SIRS subgroup, survival estimates up to 90 days were higher for responders than non-responders for both treatment groups. Estimates of RRT-free survival to day 90 were higher in the terlipressin group than in the placebo group for subjects with SIRS at baseline.

A lower percentage of subjects with SIRS at baseline in the terlipressin group were admitted to the ICU: 14 (16.7%) subjects in the terlipressin group compared with 12 (25.0%) subjects in the placebo group. SIRS subjects in the terlipressin group had a shorter mean ICU stay (6.3 days) than those in the placebo group (12.1 days).

Applying stringent criteria to define HRS-1, this study found a significant reversal of renal function deterioration in cirrhotic patients treated with terlipressin and albumin compared with patients treated with albumin alone, including patients with SIRS criteria. . This response was durable and the need for initial RRT was minimal. Therefore, terlipressin is effective in improving renal function and achieving HRS reversal in patients with HRS-1 and progressively advanced liver disease.

Example 3:

As shown in Figures 6A and 6B, the incidence of respiratory failure was increased in patients receiving terlipressin, but not in patients receiving placebo. In Figure 6B, the incidence of respiratory failure was based on the CLIF-SOFA score definition of respiratory failure. Therefore, this study evaluated whether the presence of severe or grade 3 ACLF according to the EASL-CLIF system at baseline is a risk factor for the development of respiratory failure with terlipressin use in HRS1 patients.

This study was a double-blind, placebo-controlled trial. Three hundred HRS-1 patients were randomized 2:1 to receive 1 to 2 mg i.v. of terlipressin versus placebo in 6 bolus injections per hour with albumin. HRS-1 was defined as a rapid rise in serum creatinine (SCr) to ≥2.25 mg/dL in <14 days without response to volume challenge or evidence of structural kidney disease.

All patients were graded as chronic intermediate acute liver failure (ACLF) after assessing organ failure (OF) according to EASL-CLIF criteria. All patients had at least grade 1 ACLF due to the presence of HRS-1; Grades 2 and 3 ACLF represent 2 or 3 OFs, respectively. Patients were separated into grade ≤2 and grade 3 ACLF subgroups. The effect of terlipressin versus placebo on the incidence of RF was compared between these subgroups. Table 6 shows patient population statistics and Table 7 shows baseline clinical and laboratory parameters of study patients.

Figure 5 is a graph showing the 90-day survival rate of patients treated and untreated with terlipressin according to ACLF grade. Patients with ACLF grade 3 and treated with terlipressin had a lower chance of survival than patients with ACLF grade 0–2 and treated with terlipressin or patients treated with placebo regardless of ACLF grade. Figure 6C shows that the percentage of patients with respiratory failure among patients treated with terlipressin was similar to placebo for patients with ACLF grade 0-2. The percentage of patients with respiratory failure in patients treated with terlipressin with an ACLF score of 3 was significantly higher than with placebo. Respiratory failure rates in Figure 6C were based on reports of respiratory failure during the study by the investigators.

Table 8 provides odds ratios for additional baseline parameters as predictors of respiratory failure with terlipressin use.

The results in Tables 4 to 6 indicate that terlipressin should be used with extreme caution in patients with HRS-1 and ACLF grade 3, especially those with impaired oxygen saturation. Patients with low baseline SpO ₂ are at risk for respiratory failure (RF) and increased mortality.

Example 4:

To evaluate the impact of the proposed palliative strategy on liver transplant incidence and pretransplant mortality in subjects enumerated at baseline in two previous terlipressin studies (REVERSE [Example 1] and CONFIRM [Example 2]): Analysis was performed. The remission population excluded data from subjects with baseline chronic moderate acute liver failure grade 3 and baseline serum creatinine ≥5 mg/dL, and subjects listed for transplant at baseline with a baseline MELD ≥35.

In CONFIRM, the incidence of liver transplantation by day 90 in the remission group was slightly higher in the terlipressin group than in the placebo group (24.2% vs. 22.5%) compared to the intention-to-treat (ITT) group; was lower compared to the placebo group (23.1% vs. 28.7%) (Table 9).

Similarly, the incidence of subjects listed at baseline who did not receive a transplant and died by day 90 was substantially reduced from 21.4% (12 subjects) in the overall population to 11.4% (4 subjects) in the remission population. Of the 12 subjects listed at baseline in the overall population who did not receive transplant and died by day 90, 6 subjects were in remission by excluding data from subjects with ACLF-3 and SCr ≥5 mg/dL, MELD ≥35 cutoff criteria. Two additional subjects went into remission (Table 10). In the REVERSE study, a similar effect to the relief strategy of the terlipressin group was observed.

Because of the limited number of donor organs available in the United States, only about half of all waitlist subjects in 2018 received a liver transplant within a year, and many patients died without receiving a transplant or were removed from the waitlist (Kwong 2021). For example, in 2016, 11.3% of all patients listed for liver transplantation died before receiving the transplant (Kwong 2021), the 90-day pretransplant mortality rate was 10.5% overall, and the mortality rate at 90 days was 10.5% overall for patients with a MELD score ≥35. In this case, it was 25.7% (Nagai 2018).

Pretransplant mortality rates in the remission population in the CONFIRM study and in the pooled datasets of the CONFIRM and REVERSE studies were consistent with published data for all US transplant enumerated patients. Overall, these analyzes suggest that for patients receiving terlipressin, palliative strategies have a positive impact on the incidence of liver transplantation and prevent patients listed for liver transplant from receiving a transplant due to the potential adverse effects of terlipressin. Minimize the risk of becoming

In the CONFIRM study, there was a clinically meaningful reduction in total SAEs, respiratory failure SAEs, total fatal AEs, fatal respiratory failure AEs, and overall mortality in the terlipressin group compared to the respective overall groups in the remission group (Table 11).

In CONFIRM, there was a clinically meaningful reduction in overall SAEs and incidence of SAEs due to respiratory failure in the remission group (Table 11). The between-group difference in the incidence of respiratory failure SAEs in the overall study population of 8.4% (13.5%-5.1%) was reduced to 2.8% (9.8%-7.0%) in the remission group. For the terlipressin group, the overall incidence of SAEs in the remission group was lower than that in the overall non-remission study group (61.4% vs. 65.0%, respectively). In the remission population, the overall SAE incidence in the terlipressin group was similar to placebo (61.4% vs. 59.2%, respectively).

The incidence of total AEs leading to death, fatal respiratory failure AEs, and overall mortality was substantially reduced in CONFIRM in the palliation population. The between-group difference in the incidence of respiratory failure fatal AEs in the overall study population of 7.5% (8.5%-1.0%) was reduced to 3.9% (5.3%-1.4%) in the remission group. The incidence of any AE leading to death by 30 days after treatment for the terlipressin group in the remission population was lower than in the overall population without remission (31.8% vs. 39.0%, respectively) and was also lower in the remission group than in the placebo group (31.8% vs. 36.6%, respectively). %).

In the remission group, the incidence of liver transplantation by day 90 was slightly higher in the terlipressin group compared to the placebo group (24.2% vs. 22.5%, respectively) and the transplant rate was lower (23.1% vs. 28.7%, respectively; Table 8). Importantly, pretransplant mortality through day 90 in subjects listed for transplant at baseline in the terlipressin group decreased from 21.4% in the overall population to 11.4% in the remission population (Table 10), and liver transplantation in the United States is within the range reported in all subjects listed for.

The benefit of terlipressin therapy for reversal of validated HRS, demonstrated in the overall CONFIRM study population, was also observed in the remission population (Table 12). The benefit of terlipressin over placebo was also maintained in secondary endpoints. The impact of the primary endpoints on the main clinical outcomes of renal replacement therapy (RRT) and RRT-free survival was also maintained. Similar to the overall population, in the remission population, the incidence of RRT was lower in the terlipressin group than in the placebo group at all time points through day 90.

The remission group had a similar risk of receiving RRT as the overall group, as evidenced by the proportion of subjects who received RRT by day 90 (Table 13). In these subjects, RRT-free survival remained numerically favorable in the terlipressin group compared to the placebo group.

In the entire CONFIRM population, estimates of overall survival to day 90 were numerically lower in the terlipressin group compared to the placebo group (48.2% vs. 53.5%, respectively). In contrast, in the remission population, overall survival estimates to day 90 were similar in the terlipressin group compared to the placebo group (55.3% vs. 54.9%, respectively).

The risk mitigation strategy preserved the beneficial effects of terlipressin as demonstrated in the entire CONFIRM study population (i.e., statistical significance for the primary endpoint compared with placebo, reduced incidence of RRT, and favorable RRT-free survival with terlipressin). ). In the remission group, there was a clinically meaningful reduction in risk compared to the overall group, including lower incidence of respiratory failure, overall mortality, and pretransplant mortality. Therefore, the remission population represents a population for which the benefits of terlipressin treatment outweigh the risks for complications of this rare liver disease associated with high medical need and for which there are currently no FDA-approved or proven pharmacological treatments.

Although the present disclosure has been described with reference to specific implementations, it should be understood that these implementations are merely illustrative of the principles and applications of the disclosure. It will be apparent to those skilled in the art that various modifications and changes may be made to the devices, systems, and methods of the present disclosure without departing from the spirit and scope of the disclosure. Accordingly, this disclosure is intended to cover modifications and variations that come within the scope of the appended claims and their equivalents.

Throughout this specification, reference to “one embodiment,” “particular embodiment,” “one or more embodiments,” or “an embodiment” refers to a particular feature, structure, material or characteristic described in connection with the embodiment. means included in at least one implementation of the disclosure. Accordingly, the appearance of phrases such as “in one or more embodiments,” “in a particular embodiment,” “in one embodiment,” or “in an embodiment” in various places throughout this specification necessarily refer to the same implementation of the disclosure. It does not refer to examples. Additionally, specific features, structures, materials or properties may be combined in any suitable way in one or more embodiments.

SEQUENCE LISTING <110> Mallinckrodt Pharmaceuticals Ireland Limited Jamil, Khurram Pappas, Stephen Chris Teuber, Peter <120> METHOD OF TREATING PATIENTS WITH HEPATORENAL SYNDROME TYPE 1 <130> H-IK-40001T.4 WO <150> US 17/340,765 <151> 2021-06-07 <160> 1 <170> PatentIn version 3.5 <210> 1 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> SYNTHESIZED <400> 1 Gly Lys Pro Cys Asn Gln Phe Tyr Cys Gly Gly Gly 1 5 10

Claims (48)

A method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising:
When the patient has a baseline Model End Stage Liver Disease (MELD) score of less than 35, administering a terlipressin dose to the patient by intravenous (IV) injection; and
Discontinuing or reducing the dose of terlipressin in patients with serum creatinine (SCr) ≥ 5 mg/dl and/or chronic acute liver failure (ACLF) grade ≥ 3. The method of claim 1 , further comprising obtaining the patient's baseline MELD score. The method of claim 1 , further comprising obtaining an SCr level in the patient prior to administering the terlipressin dose to determine a baseline SCr level. The method of claim 1 , wherein the patient's risk of death is reduced. The method of claim 1 , wherein the patient's position on the transplant list is not compromised. The method of claim 1 , wherein the total duration of the patient's ICU stay, non-ICU stay and/or hospital stay is shortened. The method of claim 1, wherein administration of terlipressin is continued until there is a complete or partial response. The method of claim 1 , wherein discontinuing or reducing the dose of terlipressin occurs in a patient with respiratory failure. The method of claim 1 , wherein the patient also has severe kidney disease. The method of claim 1 , wherein the patient has pulmonary edema, dyspnea, or a combination thereof. The method of claim 1 , wherein terlipressin is administered every 6 hours as an IV bolus injection over 2 minutes. The method of claim 1 , further comprising monitoring oxygen saturation of the patient during treatment with terlipressin. 13. The method of claim 12, wherein monitoring oxygen saturation reduces the occurrence of adverse events. A method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising:
When the patient has a baseline Model End Stage Liver Disease (MELD) score of less than 35, administering a terlipressin dose to the patient by intravenous (IV) injection. 15. The method of claim 14, further comprising obtaining the patient's baseline MELD score. The method of claim 14, wherein the step of discontinuing or reducing the dose of terlipressin is added in patients with serum creatinine (SCr) ≥ 5 mg/dl and/or chronic acute liver failure (ACLF) grade ≥ 3. Including, method. A method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising:
Obtaining the patient's baseline Model End Stage Liver Disease (MELD) score;
Obtaining an SCr level in the patient prior to administering a terlipressin dose to determine a baseline SCr level; and
If baseline MELD score <35, baseline SCr level <5 mg/dl, patient's ACLF grade <3, or a combination thereof, administering a dose of terlipressin to the patient. 18. The method of claim 17, wherein terlipressin is administered to the patient by intravenous (IV) injection. As a method of treating a patient with hepatorenal syndrome type 1 (HRS-1),
Administering a dose of terlipressin to the patient by intravenous (IV) injection,
Only if the patient has a baseline Model End Stage Liver Disease (MELD) score <35, the patient has a serum creatinine (SCr) <5 mg/dl, the patient has an ACLF grade <3, or a combination of these How administration occurs. 20. The method of claim 19, further comprising:
Monitoring the patient's fluid overload during treatment with terlipressin; and
Reduce or discontinue terlipressin dose if fluid overload occurs. 21. The method of claim 20, further comprising administering a diuretic to the patient. 20. The method of claim 19, further comprising measuring the patient's SCr level. 1. A method of increasing overall survival of patients with hepatorenal syndrome type 1 (HRS-1), comprising:
Obtaining the patient's baseline Model End Stage Liver Disease (MELD) score;
Obtaining the patient's SCr level to determine a baseline SCr level; and
If the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg/dl, administering a terlipressin dose to the patient. 1. A method of reducing overall ICU or hospital admissions in patients with hepatorenal syndrome type 1 (HRS-1), comprising:
Obtaining the patient's baseline Model End Stage Liver Disease (MELD) score;
Obtaining the patient's SCr level to determine a baseline SCr level; and
If the patient's baseline MELD score is <35 and the baseline SCr level is <5 mg/dl, administering a terlipressin dose to the patient. 1. A method of increasing complete response in patients with hepatorenal syndrome type 1 (HRS-1), comprising:
Obtaining the patient's baseline Model End Stage Liver Disease (MELD) score;
Obtaining the patient's SCr level to determine a baseline SCr level;
administering a terlipressin dose to the patient by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg/dl;
measuring the patient's SCr level during administration of terlipressin; and
The patient's SCr level is

Continue administering terlipressin until the level is 1.5 mg/dl. 1. A method of increasing partial response in a patient having hepatorenal syndrome type 1 (HRS-1), comprising:
Obtaining the patient's baseline Model End Stage Liver Disease (MELD) score;
Obtaining the patient's SCr level to determine a baseline SCr level;
administering a terlipressin dose to the patient by intravenous (IV) injection if the patient's baseline MELD score is <35 and the patient's baseline SCr level is <5 mg/dl;
measuring the patient's SCr level during administration of terlipressin; and
Continue administering terlipressin until the patient experiences a greater than 20% improvement in serum creatinine. 27. The method of claim 26, wherein administration continues until the patient experiences greater than a 30% improvement in serum creatinine. As a method of treating a patient with hepatorenal syndrome type 1 (HRS-1),
Administering a dose of terlipressin to the patient by intravenous (IV) injection.
and wherein if the patient is listed for liver transplantation with a MELD score ≥ 35, the patient is excluded from treatment. As a method of treating a patient with hepatorenal syndrome type 1 (HRS-1),
Administering a dose of terlipressin to the patient by intravenous (IV) injection.
and wherein the patient is treated only if the patient belongs to a patient population with a median waiting time from listing to transplant of 5.6 months or more. As a method of treating a patient with hepatorenal syndrome type 1 (HRS-1),
Administering a dose of terlipressin to the patient by intravenous (IV) injection.
A method, wherein the patient is excluded from treatment if the patient belongs to a patient population with a median waiting time from listing to transplant of 0.23 months or less. A method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising:
Reducing the population of patients eligible for treatment to a palliative population to reduce the risk selected from the group consisting of respiratory failure, serious adverse events, death, and combinations thereof; and
Administering a dose of terlipressin to patients in the palliative population by intravenous (IV) injection. A method of administering terlipressin to treat a patient having hepatorenal syndrome type 1 (HRS-1), wherein the patient is listed for transplant at a baseline Model End-Stage Liver Disease (MELD) score of less than 35, and Methods, including:
Administering a dose of terlipressin to the patient by intravenous (IV) injection; and
Discontinuing or reducing the terlipressin dose in patients with serum creatinine (SCr) level ≥ 5 mg/dl and/or chronic acute liver failure (ACLF) grade ≥ 3. 33. The method of claim 32, further comprising obtaining a SCr level in the patient prior to administering the terlipressin dose to determine a baseline SCr level. 33. The method of claim 32, wherein the patient's risk of death is reduced. 33. The method of claim 32, wherein the patient's position on the transplant list is not compromised. 33. The method of claim 32, wherein the total duration of the patient's ICU stay, non-ICU stay and/or hospital stay is shortened. 33. The method of claim 32, wherein administration of terlipressin is continued until there is a complete or partial response. 33. The method of claim 32, wherein discontinuing or reducing the terlipressin dose occurs in a patient with respiratory failure. 33. The method of claim 32, wherein the patient also has severe kidney disease. 33. The method of claim 32, wherein the patient has pulmonary edema, dyspnea, or a combination thereof. 33. The method of claim 32, wherein terlipressin is administered every 6 hours as an IV bolus injection over 2 minutes. 33. The method of claim 32, further comprising monitoring the patient's oxygenation level via pulse oximetry during treatment with terlipressin. 43. The method of claim 42, wherein monitoring oxygenation levels reduces the occurrence of adverse events. 1. A method of treating a patient having hepatorenal syndrome type 1 (HRS-1), comprising:
Obtaining baseline oxygenation level (SpO ₂ ) via pulse oximetry;
Administering a dose of terlipressin to the patient by intravenous (IV) injection if the patient is not suffering from hypoxia; and
Monitoring the patient's SpO ₂ during treatment with terlipressin. 45. The method of claim 44, wherein monitoring oxygenation levels reduces the occurrence of adverse events. 45. The method of claim 44, wherein the patient's oxygen saturation is monitored for hypoxia. 47. The method of claim 46, further comprising discontinuing or reducing the terlipressin dose if hypoxia is detected. 45. The method of claim 44, wherein the patient's SpO ₂ is monitored at least three times per day during administration of terlipressin.

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